UA114003C2 - Macrolide Derivatives, Methods for Their Obtaining, and Their Therapeutic Applications - Google Patents

Abstract

The present patent application relates to the compounds of formula (I), the method of their preparation and their therapeutic use. (I)

Description

This invention relates to macrolide derivatives, their preparation and their therapeutic use. The compounds of this invention have significant antimicrobial activity, mainly against gram-positive microorganisms, and also against mycobacteria, especially in the treatment of tuberculosis.

Due to the emergence of resistance, the creation of new antibacterial agents is necessary to make it possible to destroy or prevent the growth of mycobacteria, especially those that cause tuberculosis.

Tuberculosis is a disease that is currently still a threat to health around the world. Globally, a third of the human population is infected with Musobasiegisht ishbegscio5iv.

Despite the fact that treatment exists and that the disease is curable, TB deaths reached an estimated 1.82 million in 2008, and globally, the number of cases is increasing by 1,595 per year, with an estimated 9.4 million annually in 2008 new cases of the disease. In addition, there are difficulties associated with correct appointments and compliance with treatment protocols, as well as with the emergence of multiresistant strains of M. yshregstiov5 and5. Drug interactions also interfere with optimal treatment of AIDS and tuberculosis in patients co-infected with HIV and tuberculosis.

Common treatment regimens for combating susceptible strains of M. shregsio5i5 are based mainly on a combination of three or more often four molecules: isoniazid (IMN), rifampicin (PIR), pyrazinamide (RA) and ethambutol (EMB). These medicines are the "first line" treatment.

In recent decades, tuberculosis has acquired resistance to each of the listed molecules. Strains resistant at least to isoniazid and to rifampicin are called "multiresistant" (MOK-TV). Recently, new strains resistant to a larger number of molecules have appeared: those that are resistant to isoniazid, to rifampicin, to fluoroquinolones and to at least one injected drug of the second line are defined as "ultra-resistant" (HOK-TV) .

According to World Health Organization (WHO) estimates from 2009, 0.5 million cases of IOC-TV were detected in 2007. Other estimates report relative

From the emergence of about 11,95 multi-resistant strains among all new cases of tuberculosis.

Another therapeutic disadvantage in the treatment of tuberculosis is the interaction of rifampicin with drugs to combat HIV (human immunodeficiency virus), which is an obstacle in the treatment of patients simultaneously infected with tuberculosis and HIV. Currently available anti-HIV therapeutic guidelines approve, as first-line treatment, an antiretroviral triple

C5 therapy combining a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NRTI) with two nucleoside reverse transcriptase inhibitors (NRTIs). RI and

MMETI is metabolized under the action of SURZA4. Metabolic interactions between antiretrovirals (ATEKM) and some combined medicinal products have been demonstrated. Thus, rifampicin, which is a strong inducer of gastrointestinal and hepatic SURZA4, reduces the concentration of ATVUH.

There is an urgent need for improved treatments to combat tuberculosis. Such new anti-tuberculosis treatments must satisfy one or more of the following criteria: "must shorten the duration of treatment to improve adherence to treatment protocols and to reduce the emergence of resistant bacteria, "must be well tolerated, acting through novel mechanisms of action, and thus be effective against multi-resistant and/or ultra-resistant strains, "- should be active against tuberculosis. " should reduce the duration of treatment of latent tuberculosis (asymptomatic primary infection), and in this way solve the problem of the biological reservoir of M. tiregsitsov.

EC 2126108 ii Agpoikh ei ai. (Choigpa! oi She Ategisap Spetisa! Zosieiu 102(10), 1980, 3605) disclosed sequanamycin (A) of the following formula: (35, 45, 5B, 75, 95, 105, 118, 125, 138)-12-K4, 5-dihydroxy-4,6-dimethyltetrahydro-2H-pyran-2-yl)oxy|-7-hydroxy-2-11-(5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2- yl)oxy|pyran-2-yl)-10-((3-hydroxy-6-methyl-4-oxotetrahydro-2H-pyran-2-yl)oxy|-3,5,7,9,11,13- hexamethyl-6,14-dioxooxacyclotetradecan-4-yl) 3-methylbutanoate.

(c) id 2.on iv) shcha r, Moy o va panna O (c) y

BUT. (c) 7o is) -6.Yo0- y y -- 0 6) he (4 no no):

Said compound is disclosed herein as an antimicrobial agent and as an agent that particularly facilitates the treatment of tuberculosis. However, said compound may exhibit instability, especially in an acidic or alkaline environment, and/or may also exhibit metabolic instability, making it difficult to use as a medicinal product. Therefore, it is necessary to create compounds that will have improved and/or more active pharmacokinetic properties , which will enable their use as medicinal products.

The subject of this invention is, in particular, macrolide derivatives that have a bacteriostatic and/or bactericidal effect, mainly against gram-positive microorganisms and mycobacteria, especially against strains susceptible to Musorasiegist or Soguperasiegist, resistant to first-line antibiotics, and examples of their preparation and therapeutic use.

COMPOUNDS

The present invention relates to compounds corresponding to formula (1): (c) y

KO

9, 2 oh she ' seaanananna

R 007! () у ох зоноу - (о) -о о У ( VOM OH m where: - M represents a hydrogen atom, the -(C-0)-MA2Az group or the -(C0-0)-O-B'v group ; - 7 represents: "- a hydrogen atom, " a -C:-C-alkyl group, which is unsubstituted or substituted by one or more of the Ka groups, "- a -C3.;-cycloalkyl group, which is an unsubstituted or substituted group - MH-(C-O)-Vio or the group -MH-5O»2-Bho, "group -C3-e-heterocycloalkyl", "group -MH-(C-O)-B5; - Bi is a hydrogen atom, a -C 6 -alkenyl group, a -C 6 -alkynyl group or a -C:-C alkyl group which is unsubstituted or substituted by a -C 1-4 -fluoroalkyl group or a heteroaryl group which is an unsubstituted or substituted 3-( 3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-ylmethyl; - B" represents a hydrogen atom or a -C:-6-alkyl group; - Bz represents: "a -C3;-cycloalkyl group, which is an unsubstituted or substituted -C1-6-alkyl group, a substituted -MH-5O»2-B2h group, "- a heteroaryl group, "- an unbranched or branched -C1-6-alkyl group, which is an unsubstituted or substituted group, selected from: "group -MH-Vb, and group -MH-50"2-B"?,

"" -MH-(C-O)-Bv group, " -C3-;-cycloalkyl group, which is an unsubstituted or substituted -C3-b-heterocycloalkyl group, " -C3-e-heterocycloalkyl group, " aryl group, which is unsubstituted or substituted by one or more of the groups independently selected from a halogen atom and a -C:1-4-fluoroalkyl group, a heteroaryl group that is unsubstituted or substituted by a -C.i-C-alkyl group, a -C-C-4 group - alkoxy, a group of -C:1-4-fluoroalkyl or a group of -C3-e-heterocycloalkyl," or alternatively, one or more of the groups of C:-4--alkyl; - or alternatively, EC" and Kz, together with the nitrogen atom to which they are attached, form a -C3-e-heterocycloalkyl group selected from: aziridine, azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine; and the indicated heterocycloalkyl group is an unsubstituted or substituted heteroaryl group, and the indicated heteroaryl group is an unsubstituted or substituted -C1-4-fluoroalkyl group: - B. independently represents a group selected from: "hydroxyl group," "deuterium," a halogen atom, "" group -C3;7-cycloalkyl, " aryl group, which is unsubstituted or substituted by one or more of the groups -H9", "" heteroaryl group, " group -C3-e-heterocycloalkyl, "" group -C:- 4-Alkoxy, "groups -(0-0)-MH-B'o, "groups -MH-Vich, "groups -MH-(C-O)-Vyg," or groups -MH(ZO" 2)-Visa; - B5 is a heteroaryl group; - Ve represents a heteroaryl group that is unsubstituted or substituted by one or more halogen atoms;

Zo - IV7 represents a -C1-4-fluoroalkyl group, an aryl group or a heteroaryl group, and the specified aryl and heteroaryl groups are unsubstituted or substituted by one or more of the Ky groups; - Bv is a heteroaryl group that is unsubstituted or substituted by one or more of the K2 groups; - Be represents a halogen atom, a -C1-4-alkyloxy group, a formyl group (CHO) or a -C1-4- alkyl group that is unsubstituted or substituted by a hydroxyl group; - Vio is a heteroaryl group, which is unsubstituted or substituted by a -C-C-alkyl group; - Vii represents: "a -C30-heterocycloalkyl group, which is unsubstituted or substituted by one or more oxide groups, "- a heteroaryl group or an aryl-C:-4-alkyl group, and the specified heteroaryl or aryl groups are unsubstituted or substituted one or more of the groups independently selected from a halogen atom, a hydroxyl group, a nitro group and a -C:-C-alkyl group; - Vig represents: "" a -Ci-4-alkoxy group, "a -C1-4-alkyl group, which is unsubstituted or substituted by a -MA:"4B:i5 group or a heteroaryl group, and the specified heteroaryl group is an unsubstituted or substituted group -Ci-C-alkyl, "- a heteroaryl group, which is unsubstituted or substituted by one or more of the groups selected from the hydroxyl group and the -C.-C-alkyl group; - Wiz represents: "" group -Ci-a4- alkyl, "-Ci-4-fluoroalkyl group," aryl group, which is unsubstituted or substituted by a nitro group, "or heteroaryl group, which is unsubstituted or substituted by the group -MAch6B'?7;

Wah, Viv, Viv and Ki? each independently represents: "- a hydrogen atom," or a -C:-4-alkyl group;

Viv is a -C1-4-alkyl group or a benzyl group; 60 Bi" represents an aryl group or a heteroaryl group;

Hg is a -C1-4-alkyl group or an aryl group;

Hg represents an aryl group; - B" represents: "a halogen atom, "" a -Si-4-alkoxy group, "" a -Si-4-fluoroalkyl group, "-OSE group", "nitro group", "-MH group", and the -MNON group: with;

Ag represents: "hydroxyl group," "-Ci-v-alkyl group.

Compounds of general formula (I) may include one or more asymmetric atoms.

Therefore, they can exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, and also their mixtures, including racemic mixtures, form part of this invention.

Compounds of formula (I) can exist in the form of bases or acid addition salts. Such addition salts form part of the present invention.

These salts are conveniently prepared with pharmaceutically acceptable salts, but salts of other acids, for example, for purification or isolation of compounds of general formula (I), also form part of this invention.

Compounds of formula (I) according to the present invention also include those in which one or more of the hydrogen, carbon or halogen atoms, especially chlorine or fluorine atoms, have been replaced by their radioactive isotopes, for example, the hydrogen atom is replaced by deuterium or tritium, or the carbon atom -12 is replaced by a carbon-14 atom to replace carbon-12. Such labeled compounds are useful for metabolism studies or for pharmacokinetic studies, and also in biological or pharmacological tests as probes.

In the context of this invention: "- alkyl is a saturated, unbranched or branched aliphatic group; for example, a C-C-alkyl group is an unbranched or branched hydrocarbon chain consisting of 1-3 carbon atoms, in particular methyl, ethyl, propyl or isopropyl Similarly, the group

C-alkyl is a straight or branched hydrocarbon chain consisting of 1-4 carbon atoms, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, butyl or tert-butyl. Similarly, a C-C alkyl group is a straight or branched hydrocarbon chain consisting of 1-6 carbon atoms, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl or isohexyl. "-alkenyl is a straight or branched hydrocarbon aliphatic group that includes at least one unsaturation in the form of a double bond, and includes from 2 to 6 carbon atoms. Examples that may be mentioned include vinyl and allyl groups. "alkynyl is a straight or a branched hydrocarbon aliphatic group that includes at least one unsaturation in the form of a triple bond and includes from 2 to 6 carbon atoms. Examples that may be mentioned include ethynyl and 2-propynyl groups. "- cycloalkyl is a saturated cyclic aliphatic group containing from 3 to 7 carbon atoms. Examples that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups. "- halogen is a fluorine, chlorine, bromine or iodine atom . "fluoroalkyl is an alkyl group containing from 1 to 4 carbon atoms, where one or more of the hydrogen atoms is replaced by a fluorine atom. Examples of fluoroalkyl groups that may be mentioned include trifluoromethyl, difluoromethyl, 3,3,3-trifluoropropyl, 2, 2,2-trifluoroethyl, 2,2-difluoroethyl, 2,2,3,3-tetrafluoropropyl, 1,1-difluoroethyl and 3,3,3-trifluoro-2-"trifluoromethyl)propyl. "heterocycloalkyl is saturated or partially a saturated, monocyclic or polycyclic, optionally substituted 3-9-membered ring comprising one or more heteroatoms such as nitrogen, oxygen or sulfur atoms. Sulfur atoms can be in the form of sulfoxide or sulfone. Examples of heterocycloalkyls include pyrrolidine, morpholine, piperazine, diazetidine, dihydropyrrolidine, piperidine, azepane, imidazolidine, thiomorpholine, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, diazepane or azabicyclooctane, tropane, 3,6-diazabicyclo|3.1.O|hexane, tetrahydrofuran, 3 ,7- 60 diazabicyclo|3.3.1|nonane or tetrahydrothiophene 1,1-dioxide.

"aryl is a monocyclic or polycyclic, optionally substituted aromatic system comprising from b to 14 carbon atoms. According to one embodiment of the present invention, the aryl group comprises from b to 10 carbon atoms. If the system is polycyclic, at least one of the rings is aromatic. Examples of aryl groups that may be mentioned include phenyl, naphthyl, indanyl, tetrahydronaphthyl, anthracenyl, and azulenyl. "heteroaryl is a monocyclic or polycyclic, optionally substituted 5-14-membered aromatic system. According to one variant of the present invention, the heteroaryl is a 5-10-membered system, and includes one or more heteroatoms, such as nitrogen, oxygen, or sulfur atoms. If the system is polycyclic, at least one of the rings is aromatic.

Examples of monocyclic heteroaryls that may be mentioned include thiazole, thiadiazole, thiophene, imidazole, triazole, tetrazole, pyridine, furan, oxazole, isoxazole, oxadiazole, pyrrole, pyrazole, pyrimidine, pyridazine and pyrazine. Examples of polycyclic heteroaryls that may be mentioned include indole, benzofuran, benzimidazole, benzothiophene, benzotriazole, benzothiazole, benzoxazole, quinoline, isoquinoline, indazole, quinazoline, phthalazine, quinoxaline, naphtharidine, 2,3-dihydro-1H-indole, 2,3 -dihydrobenzofuran, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydroisoquinazoline, furoi|С3,2-с|Ipyridine, 1H-pyrrolo|2,3-В|Ipyridine or tetrahydroquinazoline. "Alkoxy is an O-alkyl group containing a saturated, unbranched or branched aliphatic chain comprising from 1 to 4 carbon atoms. Examples of alkoxy groups that may be mentioned include methoxy and ethoxy.

According to this invention, distinctive compounds are compounds of the formula (I), where U represents the -(C0-0)-B2Az group, of the formula:

Ge) (o; and L-mvovz p - tprobennnnnnnnnnttO o eta dr no o v! shk g : and (IA)

Ka o

See PTO on

M

77 where Ki, NE", Bz and 7 have the values specified for the compounds of formula (1); in the form of bases or acid addition salts.

According to this invention, distinctive compounds are compounds of the formula (I), where U is a hydrogen atom, of the formula: (c) la

From them - I, navy (in To o nt o What would 5 With (in) o

IY

(about PTO on

M

77 where Ki and 7 have the values determined for compounds of formula (1); in the form of bases or acid addition salts.

Zo According to the first variant of the formula (IA), E2 represents a hydrogen atom and Kz represents an unbranched C-C-alkyl (AK), which is unsubstituted or substituted by a group, as defined for the compounds of the formula (I), the compounds of the formula (IC) , below:

o IF) and pack izhk -2' o ozh

What is known (U (oh eto

Ka i b v i o

With (C) ( M

VIO-M on

M xx where Ki and 7 have the values specified for compounds of formula (1); in the form of bases or acid addition salts. Among the compounds of the formula (IS), distinctive compounds are the compounds of the formula (IS) given below, where AIK is a methyl substituted by a phenyl group: 1) (il kIO-M on

M

37 and Ki and 74 have the values determined for compounds of formula (1); in the form of bases or acid addition salts.

According to the second version of formula (IA), distinctive compounds are compounds of formula (IE), where

ABg2 is a hydrogen atom and Kz is a branched C-C-alkyl(i-C(CH3)2-AIK), which is an unsubstituted or substituted group, as defined for the compound of formula (1): mon

He - 2o o ta, 2 sh - 2 nanni SU o l ia o -0- t y (c) - 0 ( PTO on

M and 2 and Ki and 74 have the values specified for the compounds of formula (1); in the form of bases or acid addition salts.

Among the compounds of the formula (IE), distinctive compounds are the compounds of the formula (IC) below, where AIK is a ((phenylsulfonyl)amino|methyl group:

her

MnA- 5 - o IF) 7

Oi -mni iya -o

From pcs

Sh p. nan (3

Go) Kk Go) "no oh

BUT o o o 5-9 o- - ? (c) - so (vom on

M

/ 2 and Ki and 74 have the values specified for compounds of formula (1); in the form of bases or acid addition salts.

According to the third variant of the formula (IA), E" and Ez represent an unsubstituted group -Сч1-6- alkyl (АИК), the compounds of the formula (IEE) below: о Го! Ac

Pk iya p-9 Dik still her about how gl nano

In 6) Also (IR) - o i o - o p. ( PTO on r 2 where Ki and 7 have the values determined for compounds of formula (1); in the form of bases or acid addition salts.

According to the fourth variant of the formula (IA), Ko represents a hydrogen atom and Kz represents an unsubstituted group of -C3.;-cycloalkyl (cycloAl) of the compound of the formula (IN), below:

Go) (o); x L-mn--cyclolic

Oh yeah

What about sleep (3

Ho) Ye Ho) p. o (In) no oh pad b -- - h o - o ( ih v,o-M on ri 7 where Ki and 7 have the values determined for the compounds of formula (1); in the form of bases or acid addition salts.

According to this invention, distinctive compounds are compounds of the formula (I), where U represents a group of -(C-0)-OBs, of the formula:

(c) c) ote us - 0 ih a" p, sny t o 4.

F) you (1) -9O 9o-- - 6) ;--o

Ge (about VOM OH iv de Ki, Viv and 7 have the values determined for compounds of formula (1); in the form of bases or acid addition salts.

According to this invention, distinctive compounds are compounds of formula (I), where: - M represents a hydrogen atom, a -(C-0)-MA2Az group or a -"0-0)-OMe group; - 7 represents: "- hydrogen atom, "-C:-C-alkyl group, which is unsubstituted or substituted by one or more of the Ka groups," cyclopropyl group, cyclobutyl group, 3-(benzoylamino)cyclobutyl group, 3-

Pyrazin-2-ylcarbonyl)amino|cyclobutyl group, 3-Cmethylsulfonyl)amino|cyclobutyl group, 3-Cphenylsulfonyl)amino-cyclobutyl group, cyclopentyl group, cyclohexyl group, "« tetrahydro-2H-pyranyl group, "" group -MH-(С -O)-B5; - Bi represents a hydrogen atom, an ethyl group, a 2,2,2-trifluoroethyl group or a methyl group, which is unsubstituted or substituted by a 1,2,3-triazole group, substituted by 3-(3-fluorophenyl)-2-oxo-1 ,3-oxazolidin-5-ylmethyl group; - B2 is a hydrogen atom or a methyl group; - Bz represents: "- cyclohexyl group, 1-((phenylsulfonyl)amino|methylcyclohexyl group or 1-"Cphenylsulfonyl)amino|methyl)cyclopentyl group, - 5,6,7,8-tetrahydroquinolin-5-yl group, " - or an unbranched or branched C-4-alkyl group, which is an unsubstituted or substituted group selected from: a" -MH-Ev, and -MH-502-B?7, "-MH-(C-O)-Bv , a" 1-morpholin-4-ylcyclopentyl group, " tetrahydro-2H-pyranyl group, tetrahydrofuranyl group or morpholin-4-yl group,

From "the phenyl group, which is unsubstituted or substituted by one or more of the groups independently selected from the chlorine atom and the -CEz group, "1H-pyrrolo|2,3-b|Ipyridinyl group, 4-methyl-5,6,7, an 8-tetrahydroquinazolin-2-yl group, a 6-methoxy-1H-benzimidazol-2-yl group, a pyridinyl group which is unsubstituted or substituted by a -SE or morpholin-4-yl group," or alternatively, with one or more of the methoxy groups ; or alternatively, K" and Kz, together with the nitrogen atom to which they are bound, form a -C3-6-heterocycloalkyl group selected from: azetidine, morpholine, 4-(5-"trifluoromethyl)pyridin-2-yl| piperazine; - B. independently represents a group selected from: "hydroxyl group", "deuterium", "fluorine atom", "cyclopropyl group", "phenyl group, which is unsubstituted or substituted by one or more of the groups independently selected from the fluorine atom, methoxy group, -CH2OH group and -CHO group,

"- pyridyl group, " morpholinyl group, tetrahydro-2H-pyranyl group, "- methoxy group, "" group -(C-0)-MH-Vio, "" group -MH-Vich, "" group -MH-(C -0)-НА 2, " or groups -МН(ЗО?2)-В z; - B5 is a pyridyl group; - Ve represents a quinolyl group, and the specified quinolyl group is unsubstituted or substituted by a chlorine atom; - In? is a -SEz group, phenyl, pyridinyl, pyrazolyl, 1H-pyrrolo|2,3-

BIpyridyl or indolyl group, and the specified phenyl, pyridyl, pyrazolyl, 1H-pyrrolo|2,3-B|Ipyridyl or indolyl groups are unsubstituted or substituted by one or more of the Ky groups; - Bv represents a pyrazinyl group, and the specified pyrazinyl group is unsubstituted or substituted by one or more of the Kg groups"; - Vio represents a 1,8-naphthyridinyl group substituted by a methyl group; - Vii represents a tetrahydrothiophene-1,1-dioxide, a quinolyl, pyridyl or benzyl group, and the specified quinolyl, pyridyl or benzyl groups are unsubstituted or substituted by a chlorine atom, a hydroxyl group, a nitro group or a methyl group; - Vig represents: "tert-butoxy group", -C1-4--alkyl group , which is an unsubstituted or substituted group selected from the group -MA:4B:5, pyridyl or pyrazolyl, and said pyridyl or pyrazolyl groups are unsubstituted or substituted by a methyl group, "a pyrazinyl or pyridyl group which is unsubstituted or substituted by one or more of groups selected from a hydroxyl group and a methyl group; - Visa represents: " group -SEz,

From "a phenyl group that is unsubstituted or substituted by a nitro group," or a pyridyl group that is unsubstituted or substituted by a group -MAchv6Bi17; - Vcha, Vi», Vivi Ki7, each of which independently represents: "- a hydrogen atom, " a methyl group or an isopropyl group; - B" represents: "fluorine atom, chlorine atom, "- methoxy group, "-CE3 group, "-OCE group", "nitro group, "-MH group", and -MNON:z group; - B" represents : "hydroxyl group," - methyl group; in the form of bases or acid addition salts.

According to this invention, distinctive compounds are compounds of formula (I), where: - M represents a hydrogen atom or the group -(С-0)-MA2Bz; - 7 represents: " hydrogen atom, " methyl group, isopropyl group, 2,2-dimethylpropyl group, " CO3 group, " 2-fluoroethyl group, " - cyclopropylmethyl group, " 2-phenylethyl group, " (7-methyl -1,8-naphtharidin-2-yl)amino|-4-oxobutyl group, "2-1(2-nitrophenyl)sulfonyl|amino)ethyl group, "- cyclopropyl group, "" tetrahydro-2H-pyranyl group; bo - Bi represents a hydrogen atom, an ethyl group, a 2,2,2-trifluoroethyl group or a methyl group; - B2 is a hydrogen atom or a methyl group; - Bz represents: "- a methyl group, and 2-1(2,6-difluorophenyl)sulfonyl|amino)-1,1-dimethylethyl group, ""1,1-dimethyl-2-(14-(trifluoromethyl)phenyl |sulfonyl)amino)ethyl group, "2-I(2-fluorophenyl)sulfonyl|amino)-1,1-dimethylethyl group, "1,1-dimethyl-2-(C2-(trifluoromethoxy)phenyl|sulfonyl)amino) ethyl group, ""1,1-dimethyl-2-(114-(trifluoromethoxy)phenyl|sulfonyl)amino)ethyl group, and 2-methyl-1-(phenylsulfonyl)amino|pyran-2-yl group, and 2- methyl-1-((5-nitro-1H-pyrazol-4-yl)usulfonylamino)pyran-2-yl group, and 2-methyl-1-(trifluoromethyl)sulfonylamino)pyran-2-yl group, and 2-methyl -1-((2-nitrophenyl)sulfonyl|amino)pyran-2-yl group, "1-((5-hydroxypyrazin-2-yl)ucarbonyl|amino)-2-methylpropan-2-yl group, ""1 ,1-dimethyl-2-morpholin-4-ylethyl group, "benzyl group", "2-(4-pyridyl)ethyl group; in the form of bases or acid addition salts.

Among the compounds according to this invention, it is especially possible to specify the compounds given below: - (28, 35, 48, 58, 75, 95, 105, 118, 125, 138)-7-((benzylcarbamoyl)oxy|-2- (1-(28, ZV, 48,

BV, 6B)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy)upropan-2-yl)-10-Ш(25, ЗВ, bА)-3-hydroxy -4-(Methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-H(25, 55, 78)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxidoxacyclotetradecan-4-yl 3-methylbutanoate; - (28, 35, 48, 5, 75, 95, 105, 118, 125, 138)-7-(benzylcarbamoyl)oxy|-2-(1((28, ZA, 48,

BV, 6B)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy)upropan-2-yl)-10-Ш(25, ЗВ, bА)-3-hydroxy -4-(Methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-H(25, 58, 7H)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxyoxacyclotetradecan-4-yl 3-

Co) methyl butanoate; - (28, 35, 48, 5B, 75, 95, 105, 118, 125, 138)-12-1(25, 78)-4-cyclopropyl-2,5-dimethyl-1,4-oxazepan-7- yl|oxy)-2-(1-((2НА, ЗА, 48, 5, 6НА)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl|oxy)propane- 2-yl)-10-(25, ZB, 6H)-3-hydroxy-4-(methoxyimino)-b-methyltetrahydro-2H-pyran-2-yl|oxy)-7-4(1-((5- hydroxypyrazine-2-ylcarbonyl|amino)-2-methylpropan-2-yl)ucarbamoyl|oxy)-3,5,7,9,11,13-hexamethyl-6b,4-dioxooxacyclotetradecan-4-yl 3-methylbutanoate; - (28, 35, 48, 5, 75, 95, 105, 118, 125, 138)-7-(benzylcarbamoyl)oxy|-12-1(25, 58, 7B)-2,5-dimethyl-1, 4-oxazepan-7-yl|oxy)-2-(1-3(28, ZA, 48, 5A, 6H8)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl |oxypropan-2-yl)-10-((25, ZB, 6H8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7, 9,11,13-hexamethyl-b,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate; - (28, 35, 48, 58, 75, 95, 105, 118, 125, 138)-2-(1-МК2В, ЗА, 48, 58, 6В8)-5-hydroxy-3,4-dimethoxy-b -methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-(25, ZA, /6B8)-3-hydroxy-4-(methoxyimino)-b-methyltetrahydro-2H-pyran-2-yl |oxy)-3,5,7,9,11,13-hexamethyl-6,14-dioxo-7-(C2-(pyridin-4-yl)ethylcarbamoyloxy)-12-((25, 55, 78)- 2,4,5-trimethyl-1,4-oxazepan-7-yl|oxidoxacyclotetradecan-4-yl 3-methylbutanoate; - (28, 35, 48, 58, 75, 95, 105, 118, 125, 138)- 7-Cbenzylcarbamoyl)oxy|-12-(25,7H)-4-cyclopropyl-2,5-dimethyl-1,4-oxazepan-7-yl|oxy)-2-(1-(28, ZA, 4, 58, 6H)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10- (25, ZA, /6B8)-3-hydroxy-4 - (methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate; - (28, 35, 48, 5, 75, 95, 105, 118, 125, 138)-7-(benzylcarbamoyl)oxy|-12-((25, 78)-2,5-dimethyl-4-(2Hz) )methyl-1,4-oxazepan-7-yl|oxy)-2-(1--(28, ZA, 48, 5B8, 6B)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H- pyran-2-yl|oxypropan-2-yl)-10-(25, ZA, /6B8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3 ,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate; - (28, 35, 48, 58, 75, 95, 105, 118, 125, 138)-7-(dimethylcarbamoyl)oxy|-2-(1--(28, ZA, 48,

BV, 6B)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy)upropan-2-yl)-10-Ш(25, ЗВ, bА)-3-hydroxy -4-(Methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-60 6,14-dioxo-12-Ch(25, 58 , 7H)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxyoxacyclotetradecan-4-yl 3-

methyl butanoate; - (28, 35, 48, 5, 75, 95, 105, 118, 125, 138)-7-((benzylcarbamoyl)oxy|-12-((25, 78)-2,5- dimethyl-4-( 2-(2-nitrophenyl)sulfonyl|amino)ethyl)-1,4-oxazepan-7-yl|oxy)-2-(1-((28, ZA, 48,

BV, 6B)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy)upropan-2-yl)-10-Ш(25, ЗВ, bА)-3-hydroxy -4-(Methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate; - (28, 35, 48, 5B, 75, 95, 105, 118, 125, 138)-7-((benzylcarbamoyl)oxy!|-12-(25, 78)-4-(2-fluoroethyl)-2 ,5-dimethyl-1,4-oxazepan-7-yl|oxy)-2-(1-3(28, ZA, 48, 5A, 6H)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro- 2H-pyran-2-yl|oxypropan-2-yl)-10-(25, ZA, /6B8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy) -3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate; - (28, 35, 48, 5, 75, 95, 105, 118, 125, 138)-7-(benzylcarbamoyl)oxy|-12-((25, 78)-2,5-dimethyl-4-4- ((7-methyl-1,8-naphthyridin-2-yl)amino|-4-oxobutyl)-1,4-oxazepan-7-yl|oxy)-2-(1- (ene, ze, 4H, 5 , 6H)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl|oxy)propan-2-yl)-10-((25, ZA, bA)-3-hydroxy- 4-(Methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-6b,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate; - (28, 35, 48, 58, 75, 95, 105, 118, 125, 138)-7-Kbenzylcarbamoyl)oxy|-12-((25, 78)-4-(2,2- dimethylpropyl)-2 ,5-dimethyl-1,4-oxazepan-7-yl|oxy)-2-(1--(28, ЗА, 48, 5, 6Н)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro- 2H-pyran-2-yl|oxypropan-2-yl)-10-(25, ZA, /6B8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy) -3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate; - (28, 35, 48, 58, 75, 95, 105, 118, 125, 138)-12-(25, 78)-2,5-dimethyl-4-(2-phenylethyl)-1,4-oxazepan -7-yl|oxy)-2-(1-((2НА, ЗА, 48, 5, 6НА)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl|oxy) )propan-2-yl)-10-(25, ZB, 6H)-3-hydroxy-4-(methoxyimino)-b-methyltetrahydro-2H-pyran-2-yl|oxy)-7-4(1-( (5-hydroxypyrazine-2-ylcarbonyl|amino)-2-methylpropan-2-yl)ucarbamoyl|oxy)-3,5,7,9,11,13-hexamethyl-b,14-dioxooxacyclotetradecan-4-yl 3- methyl butanoate; - (28, 35, 48, 58, 75, 95, 105, 118, 125, 138)-2-(1-МК2В, ЗА, 48, 58, 6В8)-5-hydroxy-3,4-dimethoxy-b -methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-(25, ZA, /6B8)-3-hydroxy-4-

Zo (methoxyimino)-b-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-7-((2-methyl-1-/((5-nitro -1H-pyrazol-4-ylsulfonyl|amino)propan-2-ylcarbamoyl|oxy)-6,14-dioxo-12-Ch(25,7B)-2,4,5-trimethyl-1,4-oxazepan-7 -yl|oxyoxacyclotetradecan-4-yl 3-methylbutanoate; - (28, 35, 48, 5A, 75, 95, 105, 118, 125, 138)-7-hydroxy-2-(1--(28, ЗА, 48, 5B, 6B8)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-((25, ZA, 6B8)-3- hydroxy -4-(Methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14-dioxo-12-Ch(25, 5B8, 7B)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl 3-methylbutanoate; - (28, 35, 48, 58, 75, 95, 105, 118, 125, 138)-2-(1-MK2B, ZA, 48, 58, 6B8)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10- (25, ZA, /6B8)-3-hydroxy-4-(methoxyimino)-b-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-7- ((2-methyl-1-(Ctrifluoromethyl)sulfonyl|amino)propan-2-yl/ucarbamoyl|oxy)-6,14-d ioxo-12-((25, 78)-2,4,5-trimethyl-1,4-oxazepan-7-yl|!oxyyoxacyclotetradecan-4-yl 3-methylbutanoate; - (28, 35, 48, 58, 75, 95, 105, 118, 125, 138)-12-(25, 78)-2,5-dimethyl-4-(2-phenylethyl)-1,4-oxazepan -7-yl|oxy)-7-hydroxy-2-(1--(2H, ZA, 48, BA, 68)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2- yl|oxypropan-2-yl)-10-((25, ZB, 6H8)-3-hydroxy-4-(methoxyimino)-6- methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7 ,9,11,13-hexamethyl-b,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate; - (28, 35, 48, 58, 75, 95, 105, 118, 125, 138)-2-(1-МК2В, ЗА, 48, 58, 6В8)-5-hydroxy-3,4-dimethoxy-b -methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-(25, ZA, /6B8)-3-hydroxy-4-(methoxyimino)-b-methyltetrahydro-2H-pyran-2-yl |oxy)-3,5,7,9,11,13-hexamethyl-7-((2-methyl-1-/(2-nitrophenyl)sulfonyl|amino)propan-2-yl)ucarbamoyl|oxy)-6 ,14-dioxo-12-((25, 5A, /7H8)-2,4,5-trimethyl-1,4-oxazepan-7-yl|!oxyyoxacyclotetradecan-4-yl 3-methylbutanoate; - (28, 35 , 48, 58, 75, 95, 105, 118, 125, 138)-2-(1-МК2В, ЗА, 48, 58, 6В8)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H- pyran-2-yl|oxypropan-2-yl)-10-(25, ZA, /6B8)-3-hydroxy-4-(methoxyimino)-b-methyltetrahydro-2H-pyran-2-yl|oxy)-3 ,5,7,9,11,13-hexamethyl-7-((2-methyl-1-/(2-nitrophenyl)sulfonyl|amino)propan-2-yl)ucarbamoyl|oxy)-6,14-dioxo- 12-((25, 55.7 85)-2,4,5-trimethyl-1,4-oxazepan-7-yl|!oxyyoxacyclotetradecan-4-yl 3-methylbutanoate; - (28, 35, 48, 58, 75, 95, 105, 118, 125, 138)-2-(1-МК2В, ЗА, 48, 58, 6В8)-5-hydroxy-3,4-dimethoxy-b- methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-(25, ZA, /6B8)-3-hydroxy-4- bo (methoxyimino)-b-methyltetrahydro-2H-pyran-2-yl |oxy)-3,5,7,9,11,13-hexamethyl-7-((2-methyl-1-

Cphenylsulfonyl)amino|propan-2-ylcarbamoyl)oxy|-6,14-dioxo-12-((25, 55, 78)-2,4,5-trimethyl-1,4-oxazepan-7-yl|!oxyyoxacyclotetradecane -4-yl 3-methylbutanoate; - (28, 35, 48, 58, 75, 95, 105, 118, 125, 138)-2-(1-MK2B, ZA, 48, 58, 6B8)-5-hydroxy -3,4- dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-(25, ZA, /6B8)-3-hydroxy-4-(methoxyimino)-b-methyltetrahydro -2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-7-((2-methyl-1-

Cphenylsulfonyl)amino|propan-2-ylcarbamoyl)oxy|-6,14-dioxo-12-((25, 58, 78)-2,4,5-trimethyl-1,4-oxazepan-7-yl|!oxyyoxacyclotetradecane -4-yl 3-methylbutanoate; (28, 35, 48, 5A, 75, 95, 105, 118, 125, 138)-7-141,1-dimethyl-2-

Cphenylsulfonyl)amino|ethylcarbamoyl)oxy|-2-(2-(28, ZA, 48, 5B8, 6B8)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy) -1-methylethyl)-10-3(25, ZA, 6H)-3-hydroxy-4-(methoxyimino)-b-methyltetrahydro-2H-pyran-2-yl|oxy)x-12-(25, 78) -4-isopropyl-2,5-dimethyl-1,4-oxazepan-7-yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate ; - (28, 35, 48, 5, 75, 95, 105, 118, 125, 138)-12-(25, 5B, 7H)-4-(cyclopropylmethyl)-2,5-dimethyl-1,4-oxazepan - 7-yl|oxy)-7-(1,1-dimethyl-2-

Cphenylsulfonyl)amino|ethylcarbamoyl)oxy|-2-(2-(28, ZA, 48, 5B8, 6B8)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy) -1-methylethyl)-10-3(25, ZA, 6H)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9, 11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate; - (28, 35, 48, 5, 75, 95, 105, 118, 125, 138)-12-(25, 7B)-4-(cyclopropylmethyl)-2,5-dimethyl-1,4-oxazepan-7 -yl|oxy)-7-(1,1-dimethyl-2-

Cphenylsulfonyl)amino|ethylcarbamoyl)oxy|-2-(2-(28, ZA, 48, 5B8, 6B8)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy) -1-methylethyl)-10-3(25, ZA, 6H)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9, 11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate; (28, 35, 48, 5A, 75, 95, 105, 118, 125, 138)-7-I41,1-dimethyl-2-

Cphenylsulfonyl)amino|ethylcarbamoyl)oxy|-12-((25, 78)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)-1,4-oxazepan-7-yl|oxy) -2-(2-1(28, ZA, AB, BV, bA)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10 -((25, ZA, 6A)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b ,14-dioxooxacyclotetradecane-4-yl 3-methylbutanoate; - (28, 35, 48, 5V, 75, 95, 105, 118, 125, 138)-12-TSh(25, 55, 7H8)-4-(cyclopropylmethyl)-2,5-dimethyl-1,4- oxazepan-7-yl|oxy)-7-(1,1-dimethyl-2-

Cphenylsulfonyl)amino|ethylcarbamoyl)oxy|-2-(2-(28, ZA, 48, 5B8, 6B8)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy) -1-methylethyl)-10-3(25, ZA, 6H)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9, 11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate: (28, 35, 48, 5A, 75, 95, 105, 118, 125, 138)-7-I41,1-dimethyl- 2-

Cphenylsulfonyl)amino|ethylcarbamoyl)oxy|-12-((25, 58, 78)-4-(2,2-dimethylpropyl)-2,5-dimethyl-1,4-oxazepan-7-yl|oxy)-2 -(2-ТСШ(28, ЗА, 48, 5, 6B8)-5-hydroxy-3,4-dimethoxy-6- methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10-( (25, ZA, 6A)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14 -dioxooxacyclotetradecane-4-yl 3-methylbutanoate; (28, 35, 48, 5A, 75, 95, 105, 118, 125, 138)-7-I41,1-dimethyl-2-

Cphenylsulfonyl)amino|ethylcarbamoyl)oxy|-12-((25, 78)-4-(2,2-dimethylpropyl)-2,5-dimethyl- 1,4-oxazepan-7-yl|oxy)-2-( 2-((2H, ZNA, 4, 5, 6A)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10-(25, ZA, 6B8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14-dioxooxacyclotetradecane- 4-yl 3-methylbutanoate;

BO - (28, 35, 48, 58, 75, 95, 105, 11125, 138)-7-((1,1-dimethyl-2-morpholin-4-ylethylcarbamoyl|oxy)-2-(2-(28 , ZA, 48, 5, 6H8)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10-(25, ZA, 6B8)- 3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14-dioxo-12-((25 , 78)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl 3-methylbutanoate; - (28, 35, 48, 58, 75, 95, 105, 118, 125 , 138)-7-((2-((2,6-difluorophenyl)sulfonyl|amino)-1, 1- dimethylethyl)carbamoyl|oxy)-2-(2-((28, ЗА, АВ, БВ, бА )-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10-((25, ZA, 6A)-3-hydroxy-4-( methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14-dioxo-12-(25, 78)-2,4, 5-trimethyl-1,4-oxazepan-7-yl|!oxyyoxacyclotetradecan-4-yl 3-methylbutanoate; 60 g (28, 35, 48, 5A, 75, 95, 105, 118, 125, 138)-7- ЦП,1-dimethyl-2-(Ц4-

(trifluoromethyl)phenyl|sulfonyl)amino)ethyl|Icarbamoyl)oxy)-2-(2-1(28, ZA, 48, 58, 6B8)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H- pyran-2-yl|oxy)-1-methylethyl)-10-(25, ZA, 6B8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3 . yl 3-methylbutanoate; - (28, 35, 48, 5B, 75, 95, 105, 118, 125, 138)-7-(2-((2-fluorophenyl)sulfonyl|amino)-1,1- dimethylethyl)carbamoyl|oxy)- 2-(2-((28, ZA, AB, BV, bA)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10- ((25, ZA, 6A)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b, 14-dioxo-12-(25, 78)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl 3-methylbutanoate; (28, 35, 48, 5A, 75, 95, 105, 118, 125, 138)-7-CP,1-dimethyl-2-(C2-(trifluoromethoxy)phenyl|sulfonyl)amino)ethylcarbamoyl)oxy)- 2-(2-1(28, ZA, 48, 58, 6H)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10- (25, ZA, 6B8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14 - dioxo-12-I(25, 78)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl 3-methylbutanoate; (28, 35, 48, 5A, 75, 95, 105, 118, 125, 138)-7-CP,1-dimethyl-2-(C4-(trifluoromethoxy)phenyl|sulfonyl)amino)ethylcarbamoyl)oxy)- 2-(2-1(28, ZA, 48, 58, 6H)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10- (25, ZA, 6B8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14 - dioxo-12-I(25, 78)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl 3-methylbutanoate; (28, 35, 48, 5A, 75, 95, 105, 118, 125, 138)-7-I41,1-dimethyl-2-

Cphenylsulfonyl)amino|ethylcarbamoyl)oxy|-2-(2-(28, ZA, 48, 5B8, 6B8)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy) -1-methylethyl)-10-((25, ZA, 6H)-3-hydroxy-6- methyl-4-(2,2,2-trifluoroethoxy)imino|hetrahydro-2H-pyran-2-yloxy)-3 . yl 3-methylbutanoate; (28, Z5, AB, 58, 75, 95, 105, 118, 125, 138)-7-(41,1-dimethyl-2-

Zo Cphenylsulfonyl)amino|ethylcarbamoyl)oxy|-10-1((25, ZA, b)-4-(ethoxyimino)-3-hydroxy-6b- methyltetrahydro-2H-pyran-2-yl|oxy)-2-( 2-(Ш(28, ZA, 4, 5А8, 6Н)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2Н-pyran-2-yl|oxy)-1-methylethyl)-3,5, 7,9,11,13-hexamethyl-b,14-dioxo-12-1(25,

BV, 78)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxyoxacyclotetradecan-4-yl 3-methylbutanoate; in the form of bases or acid addition salts.

OBTAINING

The nature of the strain

You can use the strain disclosed in EC patent 2126108, deposited in

North American Research Laboratory (MEKG) under number MEM. 3892.

It is also possible to use a strain named AiPPoKiipegia airada, deposited in the German collection of microorganisms and cell cultures Sto (05M2) by the Zapoiyi-Amepii group (Zapoii Amepiii5

Oeshvspiapa Street, Ipdivigiera (k Nosp5i H8VF31, 65926 Egapkish at Maip) under identification number 51108942.

Fermentation and purification for isolation of sequanamycin of formula (A)

The process of fermentation and purification, disclosed in EC 2126108, makes it possible to isolate sequanamycin of the formula (A) from the strain AliiPoKii2pegia airaga. The process can be carried out using the following protocol. This protocol is provided as a non-limiting illustration: it can be adapted for other conditions.

Yes, the fermentation process disclosed below is carried out in a volume of 500 liters, but it can be adapted for smaller or larger quantities.

The composition of the commonly used medium for pre-cultivation (called "medium 5294") has the following composition: the pH of the medium before sterilization is 7.2.

A commonly used primary culture medium (called

"environment 5254-5ed01") has the following composition:

The fermentation process is usually carried out in the following way: 1 ampoule from Vapdie de SeyiYishez ae Tgamai (VST) in

Stage 1: Pre-cultivation 1,500 µl of BST is placed in a 300 ml conical flask containing twice 100 ml of medium 5294.

The resulting mixture is stirred for 96 hours at 28 "С

KYA

Stage 2: Pre-cultivation 2 25 ml of the culture medium from stage 1 is placed in 4 x 500 ml of medium 5294 in a 2-liter conical flask, and the mixture is then stirred for 72 hours at 28 °C in

Stage 3: Pre-cultivation 1.5 L of the culture medium from stage 2 is placed in 30 liters of medium 5294 in a 42-liter bioreactor, and the resulting mixture is then mixed and aerated for 24 hours at 28 °C without pH control.

Stage 4 (main cultivation): 30 kg of culture medium from stage C is placed in 500 liters of medium 5294-5641 in an 800-liter bioreactor, and the resulting mixture is then stirred and aerated for 9625 hours at 28 "C without controlling the pH in

Collection of cells

The fermentation process disclosed above is carried out for 500 liters, but the volume can be adapted for smaller or larger quantities. It is carried out, for example, on a scale of 7000 liters in the following way, using the same culture medium:

Pre-cultivation 1-250 ml, inoculum: one ampoule of VST.

Zo Pre-cultivation of 2-5 liters in flasks (2x2.5 liters), inoculum 0.5 956 from pre-cultivation 1.

Pre-cultivation of 3-400 liters of medium in a 600-liter bioreactor, seeding rate 1.25 95 from pre-cultivation 2.

Main culture - 7,000 liters of medium in a 10,000 liter bioreactor, seeding rate 5.7 95 from previous cultivation 3.

The fermentation process is followed by the purification process outlined below (carried out in 500 liters of the fermentation broth described above).

After fermentation is complete, the fermentation broth is separated into culture supernatant and mycelium using a cylindrical separator. As a result of the separation, about 440 liters of culture supernatant are obtained.

In separate portions, 100-120 liters of the culture supernatant containing, in addition, a macrolide (sequanamycin (A)) is injected into a column filled with an adsorption resin (a glass column filled with a styrene-divinylbenzene copolymer, with an internal diameter of 200, a length of about 180 mm, and a flow rate of 250 ml/min). Then the resin is washed with 30 95 2-propanol.

Sequanamycin (A) is isolated by eluting the contents of the column using gradient elution: 30-70 96 V for 45 minutes, 70 to V for 10 minutes, 100 906 V for 25 min.; where AAngO, B-2-propanol, modified: 1 obo MNaAs 50 g/l adjusted to pH 7). The fractions containing sequanamycin (A) are combined, and the 2-propanol is evaporated. The pH of the resulting solution is brought to a value above 7.5 and the resulting solution is extracted twice with E(Ac. The organic phases are combined and the solvents are evaporated. The resulting oil (about 10 g per 100 liters of culture supernatant) is purified on a column with silica gel (column 40 mm x 260 mm), performing a gradient elution from n-heptane to 30/70 n-heptane/pB(OAc for 45 minutes, then eluting with a mixture of 30/70 n-heptane/g(OAc) for about 40 minutes (at a flow rate of 100 ml/ Purification can be monitored using thin-layer chromatography, eluting with EAs and detecting sequanamycins (as blue spots) with a reagent such as vanillin.

According to the concentrations of sequanamycin (A) in individual 100-liter portions, about 2.5 to 3.5 g of sequanamycin (A) per load with a degree of purity of 68-75 95 (according to NMR data) are obtained.

If a higher degree of purity is desired, the resulting sequanamycin (A) can be purified again using reversed-phase chromatography on a 50 x 100 mm, 5 µm U/AgexAiapiov column. Use gradient elution with Neo (A) and acetonitrile (B) and 195 vol. MNaAs 50 g/l, bringing to pH 7 (40-60 95 V for 30 minutes, flow rate -- 140 ml/min). Chromatographic results are monitored using an electrical light scattering signal. Fractions containing sequanamycin (A) are combined and lyophilized after evaporation of acetonitrile. The yield of sequanamycin (A) after the stage of final purification is 57 95, with a degree of purity of the compound of 85 95 according to NMR analyses.

The compounds of formula (I) according to the present invention are obtained from sequanamycin of formula (A).

The method of obtaining compounds of formula (I) from sequanamycin of formula (A)

In the following stages, you can use ordinary chemical reactions, especially those that are revealed in "Sotrgepepvzime Ogdapis Tgapetoptaiyope: A Scide yuyu Eipsiypa! Stoyr Rgeragayyopv" ru

Visnaga b. And agosK, ribiiznei ru donp UmiIeu 4 opz Ips.

In the following text, the term "PO protecting group" means a group that can, first, protect a reactive function, such as a hydroxyl or amine, during synthesis, and, second, restore an intact reactive function at the end of the synthesis . Examples of protective groups, as well as methods of introducing and removing protective groups, are outlined in Rgoyesiime sSgoir5 ip Ogdapis

Zupipev, Sgeepe ei ai., 44 Edyop (Shopp UMieu b Bopv, Ips., Mem MoiKk), 2007.

In the text that follows, "Leaving group Ho" means a group that can be easily removed from a molecule by breaking a heterolytic bond, with the loss of an electron pair. Such a group can thus be easily replaced by another group, for example, during a substitution reaction. Such leaving groups are, for example, halogens or activated hydroxyl groups, such as

Zo methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate, etc. Examples of leaving groups, as well as references to examples of their derivation, are presented in Admapsei

Ogdapis Spetivigu, M.V. that and U. Magsp. battle Ediiop, Umiieu Ipiegssiepse, 2007, pp. 496-501.

According to this invention, the compounds of formula (I), where X represents the group -(C-0)-MP2H3, can be obtained according to the method, which is characterized by the fact that: the compound of formula (I), where M represents a hydrogen atom: o) u ton c) No Y x (9) o oh pad - 9 - y (c) : o / (o vom on r 2 and Ki ii 7 have the values specified for the compounds of formula (I), subject to interaction with the compound of formula (I) NMK»Hz, where K» and Kz have the values indicated for the compounds of formula (1), in the presence of a carbonyl derivative and a base.

The introduction of group U, which is the group -(C-0)-MA2Az in the compounds of formula (IV), usually includes the following four consecutive stages: » a-1) protection of the hydroxyl functions of the compound of formula (IV), " а-2) obtaining of the carbonyl intermediate from the derivative of the hydroxyl function in position 7 of the macrocycle, "- a-3) carrying out the interaction of the carbonyl intermediate with the compound of formula (II)

HMR", "а-4) removal of protective groups from hydroxyl functions.

At stage a-1), the hydroxyl functional groups of the compound of formula (IV) are protected to obtain the compound of formula (III) below, and the hydroxyl functional group in position 7 of the macrocycle (on which the group Y will be introduced) remains free: (o)

Hu sh-on ot o she tttnnkanvvannvy 1 0 g |i

Ron o hundred o ooo-- o t PI

Renny in -, with and vom OR,

Where: "Ki and 24 have the values specified for the compounds of formula (1); "- РО; and Rog independently represent a hydroxyl protecting group.

At stage a-2), the hydroxyl function in position 7 of the macrocycle of the compound of formula (1) is used to obtain the carbonyl intermediate compound of formula (IM), below

U. ov u shi

Oi sht y No nn nnny time And oh what o- y y

VOM o ove and 32-77 1 1 (M ; " Ki and 24 have the values indicated for compounds of formula (1); "| C is a leaving group; "- PO; and Rog independently represent a protective group of the hydroxyl function.

At stage a-3), the carbonyl intermediate compound of the formula (IM) is subjected to interaction with the compound of the formula (II) NMKeN", where EK" and Ez have the values indicated for the compounds of the formula (1).

Stage a-3) is usually carried out in a polar solvent, for example, dimethylformamide (DMF), usually from 10 to 48 hours and at room temperature.

At stage a-4), the protective groups in the hydroxyl functions of the compound obtained at stage a-3) are removed.

Stage a-4) is usually carried out according to the methods of removal of protective groups disclosed in Rgoiesiime sgotsr5 ip Ogdapis Spetivigu, U.B.MU. MsOtie, Riepyt Rhev55, 1973 or in Sgeepe5

Rgoiesiime sgotsmrzo ip Ogdapis Zupipezi5, bu Tpeodoga MU. Sgeepe, published in addition to Umieu 5 op

Ips., 2006.

As for stage a-1), the hydroxyl functions of the compound (IV) are protected, for example, by acetate functions. Such a reaction of the introduction of protective groups can be carried out by contacting the compound of the formula (IV) with acetic anhydride in the presence of a base, especially a nitrogenous base, for example, pyridine, at room temperature, and the hydroxyl function in position 7 of the macrocycle, on which the group B will be introduced, remains free, to obtain the compound of the formula (IPSa), below:

(c) o dream (c) by tp. n 9) not 1, peannannnt o nyk sho 0) -b o- I o x, o . ГФ) и ( v.oM o-K (Sho)

M

77 where: "Ki and 24 have the values specified for compounds of formula (1).

In the first variant of stage a-2), the compound of formula (II), as defined above, is reacted, for example, with 4-M, M-dimethylaminopyridine (OMAR) and trichloromethylchloroformate, usually in the presence of a base, especially a nitrogenous base, for example, pyridine, in a polar aprotic solvent, for example, dichloromethane, at a temperature between -20 "C and room temperature, and during a time interval between 5 and 30 hours, to obtain two carbonyl intermediate compounds of the formulas (IMo) and (IMV), below:

Muyeut 90.2 s i r NT o) g eshe i- i G u. 11 here and OI (mo

S sh t. GF) -0Ўmo0- ul / ts PTO 0 OsB, t ; where: "Ki and 24 have the values indicated for compounds of formula (1); "- РО; and Rog are independently protective groups for the hydroxyl function; or at 5-4

In the city of

SYA and with o- that

ROI | at -00-- | WITH

ШЧО / VOM ОВС, 27 -sh (vi ; where: "Ki and 24 have the values specified for the compounds of formula (1); - РО: and РО" independently represent protective groups for the hydroxyl function, for example, the acetate function.

In the second variant of stage a-2), the compound of the formula (II) is reacted, for example, with imidazole and diphosgene to obtain the carbonyl intermediate compound of the formula (II), below:

о в : ве: still no in t b, still er 007 times | (with

M y t o 4 -0Й0- B-th and POM 0 nuts (where: "Ki and 24 have the values specified for the compounds of formula (1); - РО and РО" independently represent protective groups for the hydroxyl function, for example, the acetate function.

In the third variant of stage a-2), the compound of the formula (III) is subjected to interaction, for example, with diphosgene to obtain the carbonyl intermediate compound of the formula (Мб), below: o o m y X c / o ur-o, -o

And I panny t tr d) o ta z vo hi -y 0-0 u-y ( PTO OR, ud

M- and where: "Ki and 24 have the values indicated for the compounds of formula (1); - PO: and PO" independently represent protective groups for the hydroxyl function, for example, the acetate function.

In particular, stages a-1), a-2), a-3) and a-4d can be carried out simultaneously or in reverse order. So, for example: a-1) the hydroxyl functions of the compound of formula (IV) are protected, and the carbonyl intermediate compound is obtained from the hydroxyl function in position 7 of the macrocycle due to microwave heating of the compound of formula (IV) with, for example, M,M'-carbonyldiimidazole, in solvent, for example, cyclohexane, and at a temperature between 80 "C and 100 "C to obtain a compound of the formula (XX): o y y vo 9 - m . h ro o-- o o zo

Oschnn Go)

Ka Ko t o -0Yo0- um /

M KOM o ko A boju m o x--i z where 2 and Ki have the values determined for compounds of formula (1); a-2) remove protective groups of hydroxyl functions by reacting the compound of formula (XX) with an acid, for example, hydrochloric acid, in a solvent, for example, in tetrahydrofuran, to obtain the compound of formula (XXI): (c) in which 0.7 not she buoinnnnnnny In ot 007" about (in) More)

BUT set GF)

КИ - t o -0Й5- t /

M kOhm on

IN

(XXI) with where Ki and 7 have the values determined for compounds of formula (1); a-3), the compound of formula (XXI) is subjected to interaction with the compound of formula (II) HME»B»z, where E» and Kz have the values specified for compounds of formula (1).

Step a'-3) is usually carried out in a polar solvent, for example, in dimethylformamide (DMF), in the presence of a base, for example, 1,8-diazabicyclo(/5.4.O)undec-7-ene, usually for 10 to 48 hours and at room temperature.

According to this invention, compounds of formula (I), where ХУ represents the group -(С-0)-МР2Н3, can also be obtained by a method that differs in that: p-1) compound of formula (M): o) o XX

And ME"

NU about

Oi Ko

What and OT) (M)

GF) schu -.

Wa no": o "o -y6.o- y o no ha 7 on nobE 0 M ; where: "Ki, B" and Ez have the values specified for the compounds of the formula (1); react with an oxidizing agent to obtain the compound of the formula (MI): o 6)

Hu fu ko mya, 0.2 - zebra pinnnntO (MI) vod o no» o to -00- , o ; (F) - o Y Tone vIOM

IF)

where:

You, B" and Ez have the values indicated for the compounds of formula (1); p-2) the compound of the formula (MI) obtained in this way is subjected to interaction with the compound of the formula (MI):

MH" (MI) where 27 has the values specified for compound (I) in the presence of a reducing agent, to obtain the expected compound of formula (1).

At stage p-1), the oxidation of the compound of formula (M) is carried out due to the action of an oxidizing agent, for example, sodium periodate, in a polar solvent, for example, Meon, and at a temperature between 0 and 10 "C.

In stage 6-2), the reaction of a compound of formula (MI) with a compound of formula (MI) takes place in the presence of a reducing agent, for example, sodium cyanoborohydride, in a slightly acidic medium, in a solvent such as Meon.

According to this invention, compounds of formula (I), where X represents a hydrogen atom, can be obtained according to a method characterized by the following: c-1) compound of formula (MIP): (9);

Uh OH

Go) !v, 2 i - , znan (3 o x .. (MIP)

Fo no o) "o -6 o- and o

M IF) / note 0 KOM where: "Ki has the values indicated for the compounds of formula (I), subjected to interaction with an oxidizing agent, to obtain the compound of formula (IX): (9)

Hu -oN (9) t, r. NU

Ky tv, DO OO F) od (c) (хЮ no" o "o -0 o- I o schu Y o- KOM On o where Ki has the values specified for the compounds of formula (1); c-2) obtained in the compound of the formula (IX) is reacted with the compound of the formula (MI) in the following way:

MH" (MI) with where 27 has the values specified for compound (I) in the presence of a reducing agent, to obtain the expected compound of formula (1).

Stages c-1) and c-2) are carried out under the same conditions as described for stages B-1) and p-2) above.

According to this invention, compounds of formula (I), where U represents the group -(C-0O)-O-B'v, can be obtained according to the method, which is characterized by the fact that:

Compound of formula (XXI):

c) Me

In uyeutr i o, r t her boni o "a oz - a, o (9) (9)

BUT up Go) - and t o -o o- 4

C VOM on t (XXI) where Ki and 7 have the values determined for compounds of the formula (I), are subjected to interaction with the alcohol of the formula HO-Niv (XXII), in the presence of a base.

The reaction is carried out in the presence of a mineral base, for example, potassium carbonate, at room temperature.

In particular, some compounds of formula (I) can be obtained from other compounds of formula (1). So, for example, a compound of formula (I) where 2-Me can be obtained from a compound of formula (I) where 2-H by reacting with formaldehyde in the presence of formic acid and in a solvent, for example, chloroform.

The compounds of formula (I) obtained in this way can then be isolated from the reaction medium and purified by standard methods, for example, by crystallization or chromatography.

The compounds of formula (I) obtained in this way are isolated in the form of a free base or salt using standard techniques.

Compounds of formula (II) are commercially known or obtained by methods known to those skilled in the art.

Compounds of the formula (M), where U represents the group -"C-O)MR2B"z, are obtained by reacting the compound of the formula (MIP): c) 9 sh 7 fe, san SU (c) x (c) Z

I

BUT oh that -06ЙДо0-. And (c) t o SI) no PTO on note: where Ki has the values indicated for the compounds of formula (1); with the compound of the formula (II) NMReP", where EC" and Ez have the values specified for the compounds of the formula (I), in the presence of a carbonyl derivative, according to the four stages given below: "- а-1) protect the hydroxyl functions of the compound of the formula (MI), "- а-2) receive an activated derivative due to the activation of the hydroxyl function in position 7 of the macrocycle, - а-3) interact the activated derivative with the compound of formula (II)

НМА»А»з "- а-4) do not necessarily remove the protective groups in the hydroxyl functions.

Zo At stage a-1), the hydroxyl functions of the compound of the formula (MI!) are protected, obtaining the compound of the formula (X) (the hydroxyl function in position 7 of the macrocycle, on which the group Y will be introduced, remains free):

in)

Hu ton

He) lo still tver 007 that Yi oya-. -o -o v9-- and c) -oa o

RO OM ovo,

РО, where: "Ki has the values indicated for compounds of formula (1); "РОи, РО», RaОзи Ра independently represent protective groups of hydroxyl functions.

At stage a-2), a carbonyl intermediate compound is obtained from the hydroxyl function in position 7 of the macrocycle of the compound of formula (X), especially one or more of the carbonyl intermediate compounds of formula (XI) below: o

H o -- 211 5

B y b 2 s p 007 (vi she ot for sb o-- y ge -0 (Xi) reson VOM sove,

ROB, where: "Ki has the values specified for the compounds of formula (1); "| C is a leaving group; "ROi, RO", Raz and Rol independently represent protective groups of hydroxyl functions.

At stage a-3), the carbonyl intermediate compound obtained at stage a-2) is subjected to interaction with the compound of formula (II) NMKeR", where EC" and Ez have the values indicated for compounds of formula (1).

Stage a-3) is usually carried out in a polar solvent, for example, in dimethylformamide (DMF), usually within 10 to 48 hours and at room temperature.

At stage 8-4), the protective groups in the hydroxyl functions of the compound obtained at stage a-3) are removed.

Stage a-4) is usually carried out according to the method of removal of protective groups disclosed in

Rgoiesiime Stotsr5 ip Ogdapis Spetivigu, U.E.MU. MsOtiye, Riepyt Rheb55, 1973 or in Ogeepe5

Rgoiesiime Stgoyrz ip Ogdapis 5upipeziz, Bu Tneodoga M/. Steepe ririiznei Bu dop U/Pieu b op

Ips., 2006.

In the first variant of stage a-1), the hydroxyl functions of the compound (MI!) are protected, for example, by acetate functions. The specified reaction of the introduction of protective groups can be carried out by reacting the compound of the formula (MI) with acetic anhydride in the presence of a base, especially a nitrogenous base, for example, pyridine, at a temperature usually in the temperature range from room to 160 "C, and the hydroxyl function is in position 7 of the macrocycle , on which the group B will be introduced, remains free until the compound of formula (Xa) is obtained below:

(c) o 1, y, SHU o o to t

Iz r o okh "o -b o o. 16) o y I (c) ;t o v.oM 5-6 ri: (Xa) (c) where Ki has the values indicated for the compounds of formula (1).

In the second variant, stage a-1) usually includes the following three successive stages a-1-1), a-1-2) and a-1-3): - at stage a-1-1) hydroxyl functions of the compound of the formula (MIII ) are protected by acylimidazole functions to obtain the compound of the formula (XII), by reacting the compound (MI!) with 1,1'-carbonyldiimidazole in a polar aprotic solvent, for example, toluene, for from minutes to 3 hours and at a temperature from room to 80 "С : c) x-u - he 9) z, 2 We i . penennnnnyanO mah (c) Kto shi no More 0: o to -0-- y o -0 o) a and vom o 0o-4 oto m (hi )

Cl 10 where Ki has the values specified for compounds of formula (1).

Tertiary alcohol mycarose reacts with acylimidazole of secondary alcohol at position a to obtain carbonate. - at stage a-1-2) protective groups of hydroxyl functions are removed by reacting the compound of the formula (Xiii) with an acid, usually hydrochloric acid, in a polar aprotic solvent, for example, tetrahydrofuran (THF), usually at room temperature and within 2 to 24 hours, for example, to obtain the compound of the formula (XII) below: the values specified for the compounds of the formula (1) - at stage a-1-3y, the secondary hydroxyl functions of the compound of the formula (XIII) are protected by acetate functions, carrying out the interaction of the indicated compound with acetic anhydride in the presence of a base, especially a nitrogenous base, for example, pyridine, of course at room temperature and within 5 to 48 hours, for example: (c) ия о -оН

Ob, 2 p us. 0 o'clock lat Mon

K) -th o More

ОО... о -д что ив -о / (in; in) Оу; vom o 0-4 o-С o : snu de Ki: has the values specified for the compounds of formula (1).

In the first variant of stage 4-2), the compound of formula (Xa), as defined above, is reacted with 4-M, M-dimethylaminopyridine (OMAR) and trichloromethylchloroformate, usually in the presence of a base, especially a nitrogenous base, for example, pyridine, in a polar aprotic solvent, for example, dichloromethane, at a temperature between -20 C and 5" C for a period of time between 30 minutes and 10 hours, and then at room temperature for 5 to 30 hours, to obtain two carbonyl intermediate compounds of formulas (Xi) and ( HID), below:

Ф) (c) - more / that it o, o X b, 2 it

What " ladies (U o o still o sho sg - o o o; o -b o- o - o - o i! (c) o /.- vm 0-6 7: (Ho) r and (c)

SI with c) hu .: g. o, p 9 oh (c) IF) or (FI Z. - yiv) o o po -( o0o-- o - (c) o u vIoM 9-4 o: (HIV )

UA,

where Ki has the values specified for compounds of formula (1).

In the second version of stage 4-2), the compound of the formula (KHIM) is reacted, for example, with OMAR and trichloromethyl chloroformate, usually in the presence of a base, especially a nitrogenous base, for example, pyridine, to obtain two carbonyl intermediate compounds of the formulas (KHM) and (KHMI) , below: (o; - xx / i Go) x o more

IF) GO) or Go) t, - o o o yo) -0o- i o - o o o m o i eye m i /

SI oh and well he oh, .

OO not even virgins (0) oh and she

From Ж, о: о "о -9605- И (о; (ХМ) в о kОм (в) оо : ! that where Ki has the values specified for the compounds of formula (1).

In the third version of stage 4-2), the compound of the formula (KHIM) is reacted, for example, with 1,1-carbonyldiimidazole to obtain the carbonyl intermediate compound of the formula (KHMI), below: o (F) x gm y M

HUH I h-and oh

IF) HF) schi Ho) that - o o oto -b o-- J 6) - o o (in; also (HMIII) kOm (o) oo i in where Ki has the values specified for the compounds of formula (1).

In the fourth variant of stage 4-2), the compound of the formula (CHM) is subjected to interaction, for example, with diphosgene to obtain the carbonyl intermediate compound of the formula (CHMII), below:

at! 6) uch: o, o 0, s e v, penny (6) o e o no -i o - NI o. o what) -6 shF 0. and o) o- o / o and KIM 0-4 (XM) ooo: where Ki has the values specified for the compounds of formula (1).

Compounds of formula (MI) are commercially available, known or prepared according to methods known to those skilled in the art, and may be in the form of a salt such as the hydrochloride.

Compounds of the formula (MI) are prepared by reacting sequanamycins (A) with a compound of the formula (XIX) NaMONV!I, where Ki has the values indicated for the compounds of the formula (I), in the presence of a base, for example, triethylamine, if necessary. The reaction is carried out in a solvent, for example, in methanol.

Compounds of formula (XIX) are commercially available, known or prepared according to methods known to those skilled in the art, and may be in the form of a salt such as the hydrochloride.

Compounds of formula (XXIII) are commercially available, known or are obtained according to methods known to specialists in the field.

According to other aspects, the object of this invention are also compounds of formulas (M) and (MIP).

These compounds are useful as intermediate compounds for the synthesis of compounds of formula (I).

Thus, the object of this invention is compounds of formula (M): (c) (8) y

Ku ME"

NU c)

Oh pcs

Co., ATO) (M)

GO) "In !;. "M;

NO". Ge! "о -0о0- - о и о / о он no7: MOM where: "Ki, B" and Ez have the values specified for the compounds of formula (1).

The object of this invention is also compounds of the formula (MI):

F) in -on

Go) p 2 and the paths Z (M)

FI o) no» o) "o -0 ShshchD6- - (F) o and nogE 0 KOM with where:

"Ki has the values specified for compounds of formula (1).

Examples of obtaining compounds of formula (I) from sequanamycin of formula (A)

The following examples disclose the preparation of certain compounds according to the present invention.

The presented examples are not limiting and are merely illustrative of the present invention.

The following abbreviations are used in the derivation examples and in the examples:

Es: ethyl acetate

TI C (TLC): thin-layer chromatography

SNFeIiz»: chloroform

OSM: dichloromethane

OME (DMF): M, M-dimethylformamide

TEA: triethylamine

MaIO:: sodium metaperiodate, sodium periodate

K»bO:z: potassium carbonate

Meon: methanol

Ma5o»: magnesium sulfate

Mmavnzsm: sodium cyanoborohydride

Weight: sodium chloride

Mmansoz: sodium bicarbonate

Ma?5O»:: sodium sulfate

MNASI: ammonium chloride

MNAAc: ammonium acetate

TNE (IF): tetrahydrofuran

CT: room temperature

Materials and methods

Synthesis reactions are monitored by TLC. The plates are made of glass and coated with Megsk 60 E254 silica gel. After elution, the plate is studied under ultraviolet light with a wavelength of 254 nm, and then detected by treating with a solution of the mixture: 5M sulfuric acid/water followed by heating.

Reactions using microwave radiation are carried out using

From the source of microwaves Vioiade Ipyiag 8 EHR. The obtained products are purified, if necessary, using the Vioiade 5P-1 chromatograph or the Zroi 2 chromatograph from MegoK. Columns with silicon dioxide 15-40 μm from MegeskK (2.5 g to 400 g) are used as columns.

Analyzes

Mass spectrometry (MS):

Method a: "Spectra are recorded using a Umayiete high-performance liquid chromatography device

ORI 6-5OYU; "Ionization: electrospraying in positive and/or negative mode (Eb-/-); "Chromatographic processing conditions: "Column: Asdiyu VEN C18-1.7 μm - 2.1x50 mm." Solvents: A: HgO (0, 1 95 formic acid) In: CH3CM (0.1 95 formic acid), " Column temperature: 50 "C, " Flow rate: 1 ml/min, " Gradient (2 min): from 5 95 to 5095 V for 0, 8 minutes; 1.2 min: 100 95 V; 1.85 min: 100 95 V; 1.95:5 95 V.

Method B: "Spectra are recorded using an Umayiete high performance liquid chromatography device

ORI 6-5OYU; "Ionization: electrospraying in positive and/or negative mode (Eb-/-); "- Conditions of chromatographic processing: "Column: Asdiyu VEN C18-1.7 μm - 2.1x50 mm, "" Solvents: A: HgO (0 ,1 95 formic acid) In: CH3CM (0.1 95 formic acid), " Column temperature: 50 "С, " Flow rate: 0.8 ml/min, " Gradient (2.5 min): from 5 95 to 100 95 V for 1.8 min; 2.40 min: 100 95 V; 2.45 min: 100 95 V; from 100 95 to 5 95 V for 0.05 min.

Method c: "Spectra are recorded using the Umayeg5 20 device); "Ionization: electrospraying in positive and/or negative mode (Eb-/-); 60 "- Chromatographic processing conditions:

"Column: KhVgidde C18-2.5 μm - C3x50 mm, "« Solvents: A: HgO (0.1 95 formic acid) B: CH3CM (0.1 95 formic acid), " Column temperature: 70 "С, " Flow rate: 0.9 mL/min, " Gradient (7 min): 5 95 to 100 95 V over 5.3 min; 5.5 min: 100 95 V; 6.3 min: 5 95 V.

Method a: "Spectra are recorded using the device of ultra-efficient liquid chromatography Umasgetg5

ORI 6-5OYU; "Ionization: electrospraying in positive and/or negative mode (Eb-/-); "- Chromatographic processing conditions: "Column: Asdiyu VEN C18-1.7 μm - 2.1x50 mm, "- Solvents: A: HgO (0 ,1 95 formic acid) In: CH3CM (0.1 95 formic acid), " Column temperature: 50 "C, " Flow rate: 1 ml/min, " Gradient (5 min): from 5 95 to 100 95 V during 4.2 min; 4.6 min: 100,905 V: 4.8 min: 5,95 V.

The method is:

Spectra are recorded using the device Umayegv5 20); "Ionization: by electrospray in positive and/or negative mode (Eb'/-); "Chromatographic processing conditions: "Xeiesia column C18 3.5 μm - Хх50 mm, "« Solvents: A: HgO (0.1 95 formic acid) B: CH3CM (0.1 95 formic acid), " Column temperature: 60 "С, " Flow rate: 1 ml/min, " Gradient (7 min): from 10 95 to 100 95 V for 4.5 min; 4.85 min: 100 95 V; 6.5 min: 10 95 V.

The method is "Spectra are recorded on Adiiepi 6110 or Zpitaidla 2010 devices; "Ionization: electrospraying in positive and/or negative mode (Eb-/-); Hiitaije C18 C18 column, 2.1x30 mm, Solvents: A: HgO (4 l) and TEA (1.5 ml); In: SNZSM (4 l) and TEA (0.75 ml),

From " Column temperature: 50 "C, " Flow rate: 1.2 ml/min, " Gradient (2 min): from 10 95 to 80 95 V for 0.9 min; 1.5 min: 80 95 V; 1.51 min: 10 95 V; 2 min: 10 95 V.

Method d: "Spectra are recorded on the device 5pitaidy 2010; "Ionization: electrospraying in positive and/or negative mode (Eb-/-); " Column Megsk KR-18ee 2x25 mm, " Solvents: A: H2HO (41) and TEA (1.5 ml); B: SNZSM (4) i- TEA (0.75 ml), " Column temperature: 50 "C, " Flow rate: 1.0 ml/min from 0 to 0.08 min; 1.5 ml from 0.08 to 1.50 min, " Gradient (1.50 min): fromO to 0.08 min 5 905 V; from 5 95 to 95 95 V from 0.08 to 0.7 min; 1.10 min: 95 95

V; 1.11:5 95 V; 1.5 min: 5,925 V.

Method n: "Spectra are recorded on Adiiepi 6110 or Zpitaidli 2010 devices; "Ionization: electrospraying in positive and/or negative mode (Eb-/-); " Hipaie column C18 3 μm, 2.1x30 mm, " Solvents: A: H2HO (41) and TEA (1.5 ml) B: SNZSM (4Y) and TEA (0.75 ml), " Column temperature: 50 " C, "Flow rate: 1.2 mL/min," Gradient (2 min): 30 95 to 90 95 V over 0.9 min; 1.5 min: 90 95 V; 1.51 min: 30 95 V; 2 min: 30 95 V.

The method: "Spectra are recorded on the Adiyepi 6110 device; "Ionization: electrospraying in positive and/or negative mode (Eb'/-); "Columns A: Yuigazpei! C18 Z μm 2.1x30 mm; B: Khbhide KR18 5 μm, 2.1x50 mm, " Solvents: A: H2gO (41) and TEA (1.5 ml) B: SNZSM (4Y) and TEA (0.75 ml), " Column temperature: 50 "C, " Flow rate: 1.2 ml/min, " Gradient (2 min): from 10 95 to 80 95 V for 0.9 min; 60 1.5 min: 80 95 V; 1.51 min: 10 95 V; 2 min: 10 95 V.

IN NMR nuclear magnetic resonance on protons

H NMR spectra were recorded on a VgyKeg Amapse spectrometer (300 MHz, 400 MHz, 500 MHz, or 600 MHz) in deuterated DMSO. Chemical shifts are expressed in units of b (ppm) using tetramethylsilane (TM5) as an internal standard. To interpret the spectra use the following abbreviations: 5 - singlet, y - doublet, y - triplet, d - quartet, acipi - quintet, zehi - sextet, da - doublet of doublets, 44y - doublet of doublet of doublets, t - multiplet, ah - axial, edptsai. - equatorial.

Examples of receipt

Preparation of intermediate compounds for the following examples:

Production example 1: (28, 35, 48, 5В8, 75, 95, 105, 118, 125, 138)-12-Ш(28, 48, 55, 65)-4,5-dihydroxy-4,6-dimethyltetrahydro -2H-pyran-2-yl|oxy)-7-hydroxy-2-(1-3(28, ZA, 4, 5, 6H)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H- pyran-2-yl|oxypropan-2-yl|-10-((25, ZA, / 6B)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)- 3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate (c) b --OH

12 g of sequanamycin(A) are placed in 175 ml of MeOnH with stirring, and 5.3 ml of TEA, and then add 3 g of methylhydroxylamine hydrochloride, in the specified order. Stirring is continued at RT for 20 hours, and then the MeOH is evaporated in vacuo. The crude reaction product is placed in 150 ml of OSM and washed with 100 ml of water and then with 100 ml of a saturated aqueous solution of Masi. Aqueous phases are extracted with 150 ml of UOSM. The organic phases are combined, dried over

Maz5o", filtered and concentrated in a vacuum. 12.7 g of the obtained product is suspended in 70 ml of a mixture (2/1) of petroleum ether (40-602С)/zopropanol. The resulting mixture is heated to 709C, the resulting insoluble material is filtered while it is hot, and then the product is left to settle at room temperature for 20 hours. The product is filtered under vacuum and washed with 20 ml of a mixture (2/1) of petroleum ether (40-602С)/isopropanol. The precipitate is dried in a vacuum at 352C, obtaining 10.62 g of the expected product.

MS: the method of

Retention time Tg (min) - 4.87; |Ma-Ma|: t/2 1014; (IM-NANSO»NI: t/2 1036.

Zo IH NMR (500 MHz, m.h., OM5O-av): 0.81 (d, U-6.8 Hz, ZN); 0.93-1.01 (m, 15Н); 1, 07 (d, 9U-7.0 Hz,

ZN); 1.09-1.13 (m, 9H); 1.17 (d, 9U-6.0 Hz, ZN); 1.18 (d, U-6.0 Hz, ZN); 1.24 (c, ZN); 1.44 (dd, U-10.61 14.4 Gu, 1H); 1.68-1.76 (m, 2H); 1.81 (d, U-14.4 Hz, 1H); 1.688 (dd, 9U-11.51 15.9 Hz, 1H); 1.96-2.06 (m,

ZN); 2.07-2.20 (m, 4H); 2.73 (quintet, U-7.0 Hz, 1H); 2.81 (t, U-9.0 Hz, 1H); 2.89-2.97 (m, 2H); 3.03 (ddd, 9U-2.51 7.3 and 9.5 Gu, 1H); 3.18 (sq., U-6.8 Hz, 1H); 3.34-3.36 (m, 2H); 3.37 (c, ZN); 3.45 (c, ZN); 3.52 (dqv., U-6.2 and 9.4 Hz, 1H); 3.60 (c, 1H); 3.62-3.65 (m, 1H); 3.66 (t, U-2.5 Hz, 1H); 3.71-3.77 (m, 1H); 3.78 (m, 1H); 3.80 (c, ZN); 3.81-3.84 (m, 1H); 3.87 (m, 1H); 4.39-4.46 (m, ZN); 4.50 (c, 1H); 4.72 (d, 9-8.3 Hz, 1H); 4.78 (d, U-8.3 Hz, 1H); 4.84 (d, 9-7.3 Hz, 1H); 4.87 (d, 9U-3.8 Hz, 1H); 5,19 (d, 9-44

Hz, 1TN).

Preparation example 2: benzylcarbamate (28, 35, 48, 5, 75, 95, 105, 118, 125, 138)-7-(benzylcarbamoyl)oxy|-12-((28, 48, 55, 65)-4, 5-dihydroxy-4,b-dimethyltetrahydro-2H-pyran-2-yl|oxy)-2-(1-(28, ZNA, 4, 5, 6H)-5-hydroxy-3,4-dimethoxy-6- methyltetrahydro-2H-pyran-2-yl|oxy)propan-2-yl)-10-(25, ZA, 6H8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl |oxy)-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl 3-methylbutanoate.

(at)

We x M where 0.2 -

K still o ry no" o "o -0o0- y o o i no MeoM ON

BUT:

Example of obtaining 2.1: 9) iya se ОН о r, Чо и о пн, became ve vo ВІТ о что -и ) I (c) о)

Op o - o o- /-9 y- o

He) t / Meom 0-X noya: 8.6 g of the compound obtained in preparation example 1 is placed in 86 ml of pyridine, and 8.27 ml of acetic anhydride is added. The resulting mixture is stirred for 24 hours at room temperature, and then the pyridine is concentrated in vacuo. Add 150 ml of OSM, and the resulting mixture is washed with 120 ml of a 1N solution of HCI, and then with 100 ml of a saturated aqueous solution of Masi. Aqueous phases are extracted with 150 ml of OSM. The organic phases are combined, dried over Mag 5 O 4 , filtered and then evaporated to dryness. 9.75 g of the expected product are obtained.

MS: method a

Retention time Tg (min) - 1.27; |MaeMa|": t/2 1140.

IN NMR (400 MHz, m.h., OM5O-av): 0.81 (d, U-6.8 Hz, ZN); 0.91-1.01 (m, 15Н); 1.02 (c, ZN); 1.03-1.12 (m, 12Н); 1.21 (d, U-6.1 Hz, ZN); 1.24 (c, ZN); 1.50 (dd, 9U-10.51 and 14.5 Hz, 1H); 1.72-1.94 (m, 6H); 1.96-2.10 (m, 8H); 2.12-2.18 (m, ZN); 2.22 (c, ZN); 2.77 (m, 1H); 3.02 (dd, U-2,718.1 Hz, 1H); 3.08 (m, 1H); 3.16 (sq., U-7.1 Gu, 1H); 3.36 (m, 1H); 3.39 (c, ZN); 3.41 (c, ZN); 3.45 (m, 1H); 3.63-3.72 (m, 2H); 3.76 (width, 4H); 3.80 (m, 1H); 3.85 (t, 9U-2.7 Hz, 1H); 4.11 (m, 1H); 4.17 (c, 1H); 4.35 (dd, 9U-2.7 and 10.3 Hz, 1H); 4.42 (m, 2H); 4.52 (d, 9-81 Hz, 1H); 4.63 (d, 9U-7.3 Hz, 1H); 4.69 (d, U-9.0 Hz, 1H); 4.75 (d, 9-9.0 Hz, 1H); 4.93 (d, 9U-4.0 Hz, 1H); 5.00 (d, 9U-7.3 Hz, 1H).

Preparation example 2.2: c) hu ZON ge) tr p o zh o p, DDT tt - o ol He) to b v Я o 0-0 5 He) o M ok 4 eo- o nak 1 g of the compound obtained in preparation example 2.1, put in 20 ml of pyridine in a microwave reactor, and add 1 ml of acetic anhydride and 50 mg of 4-dimethylaminopyridine.

The resulting solution is heated for 2 hours at 15523 using a microwave

From radiation. The reaction mixture is poured into 50 ml of OSM and washed with 30 ml of 1N HCl solution, and then with 30 ml of water. Aqueous phases are extracted twice with 50 ml of OSM. The organic phases are combined, dried over Mg5O, filtered and then evaporated to dryness under vacuum. The residue, 1.1 g of a brown foam, was purified using MegsK cartridge chromatography (50 g of silica 15-40 μm), eluting with a mixture of 40/60 EIAs/heptane. 0.69 g of the expected compound are obtained.

MS: method a

Holding time Tut (min) - 1.29; |MaMa|": t/2 1182.

IN NMR (500 MHz, m.h., OM5O-av): 0.81 (d, 9U-6.9 Hz, ZN); 0.91-1.02 (m, 18Н); 1.06 (m, 6H); 1.10 (d, U-6.9 Hz, ZN); 1.19-1.26 (m, 6H); 1.35 (c, ZN); 1.44 (dd, 9U-10.5114.5 Hz, 1H); 1.79 (m, 1H); 1.84-2.09 (m, 15Н); 2.11-2.18 (m, 6H); 2.73 (m, 1H); 3.02 (dd, 9U-2.7 and 7.8 Hz, 1H); 3.06-3.20 (m, ZN); 3.35-3.42 (m, 8H); 3.60-3.69 (m, 2H); 3.77 (width, 4H); 3.80 (m, 1H); 3.85 (t, U-2.7 Hz, 1H); 4.16 (m, 1H); 4.36 (dd, uU-2.7 and 9.9 Hz, 1H); 4.48-4.53 (m, ZN); 4.59 (d, 9-71 Gu, 1H); 4.73-4.80 (m, 2H); 4.87 (d, 94.3 Hz, 1H); 5.00 (d, 9-71 Gu, 1H).

Example of obtaining 2.3:

SI |c) o (o)

Her. Caviar in:

ХУ Ко) Ге) Х р у У or рН р; as; Sl y nku o KO o li, misses o Ky o t, Mr. - U | -4 U ope o pa bych o pad -b-- o -60-- o o-4 y o o-Й 5 o e mes 4 o Mmeo- ой ой: ой: ом. in. (2.3.a) (2.3.6) 3.5 g of the compound obtained in preparation example 2.2, dissolved in 140 ml of OSM, and 3.6 ml of pyridine are placed in an argon atmosphere with stirring. The resulting yellow solution is cooled to -10 "C, followed by rapid addition of trichloromethyl chloroformate (diphosgene), and stirring is continued at -10 "C for 3 hours. Then add 0.368 g of 4-dimethylaminopyridine dissolved in 10 ml of OSM. The temperature of the reaction mixture is maintained at -52C for the next 30 minutes, then allowed to warm to room temperature, and stirring is continued for 20 hours. The solvent is evaporated and 150 ml of EIOAc is added to the crude reaction product. The resulting mixture is stirred for 15 minutes at room temperature, and the resulting precipitate is then filtered. The precipitate is washed with 70 ml of EOAc, and the resulting filtrate is evaporated to dryness under vacuum. 3.92 g of a mixture of expected compounds (structures 2.3.a and 2.3.5) are obtained. The resulting mixture is used without processing at the next stage.

Preparation example 2.4: a) Condensation of amine (benzylamine)

1.5 g of the compound obtained in preparation example 2.3 is placed in 30 ml of DMF in a 100 ml round-bottom flask, and then 0.1 ml of benzylamine is added. The resulting mixture is stirred for 24 hours at room temperature, followed by the addition of 100 g of ice and 100 ml of water. The resulting precipitate is filtered under vacuum and washed with a minimum amount of water. After drying in a vacuum at 3523, 1.18 g of the expected compound are obtained. p) Removal of protective groups 1.18 g of the compound obtained in the previous stage is placed in 20 ml of Meon, and 0.63 g is added to it

K»bOz. The heterogeneous medium is stirred at room temperature for 3 hours and then filtered through a funnel made of sintered glass Me4. The resulting filtrate is placed in 100 ml

ECOAs and washed with a saturated aqueous solution of Masi. The organic phase is dried over Mox, filtered and then evaporated to dryness. 1.05 g of the crude compound is obtained, the resulting product is purified using chromatographic treatment on a MegskK column (30 g of silicon dioxide 15-40 μm), using a gradient elution with a mixture from 30/70 to 60/40 E(OAc/heptane.

0.466 g of the expected product is obtained.

MS: the method of

Tg retention time (min) - 5.21; MANI": t/2 1125; main peak: t/2 981 |M-NANSO2NI: t/2

IN NMR (500 MHz, m.h., OM5O-av): 0.80 (d, U-6.8 Hz, ЗН); 0.92 (d, U-6.8 Hz, ZN); 0.96-1.02 (m, 9H); 1.05 (m, 6H); 1.08-1.15 (m, 9H); 1.18 (m, 6H); 1.67-2.18 (m, 10Н); 1.73 (c, ZN); 2.18 (d, 9U-6.8 Hz, 2H); 2.59-2.67 (m, 1H); 2.80 (t, U-8.8 Hz, 1H); 2.92 (dd, 9U-2.7 and 8.1 Gu, 1H); 2.94-3.06 (m, ZN); 3.27-3.35 (partially masked m, 1H); 3.38 (c, ZN); 3.41 (d, 9U-9.8 Gu, 1H); 3.45 (c, ZN); 3.49-3.56 (m, 1H); 3.60-3.72 (m, 4H); 3.80 (c, ZN); 3.82 (m, 1H); 3.87 (width, length, U-5.4 Gu, 1H); 4.01-4.17 (m, ZN); 4.34-4.39 (m, 2H); 4.45 (d, 9U-7.8 Hz, 1H); 4.50-4.57 (m, 2H); 4.85 (d, 9U-7.3 Hz, 1H); 4.93 (d, 9-24 Hz, 1H); 5.13 (width, 1H); 7.18-7.36 (m, 6H).

Example of obtaining 3: b n o. (7

GF) gu xx MN dra still vo) NO m o, oso

Om WHAT KE t, DILO OO)

What. o , o o "o no o -b o-- ka o / no meoM on no:

Example of obtaining 3.1: (c) hu se ОН o, r U t o tsk o pa ee nn vysh

Opch o "a ov y o --o / (v; a and meom 0-4

M

111 g of the compound obtained in preparation example 1 is placed in 220 ml of toluene. Add 9.07 g of 1,1"-carbonyldiimidazole, and the reaction mixture is then heated at 60 "C for 45 minutes.

The mixture is then left to cool to room temperature, and the precipitate is filtered off and washed with toluene. The toluene phase is washed with 100 ml of water and then dried over Ma5O.

After filtering, the solvent is evaporated to dryness and 14.26 g of the expected product is isolated.

MS: method a

Tg retention time (min) - 1.22; MANI": volume 2 1206; IM-NANSOONI: volume 1250.

NMR NMR (500 MHz, m.h., OM5O-av): 0.80 (d, U-6.8 Hz, ZN); 0.83 (d, 9U-7.3 Hz, ZN); 0.90 (d, 9U-6.8

Hz, ZN); 0.98 (dt, U-3.2 and 6.4 Hz, 9H); 1.03 (d, U-7.3 Hz, ZN); 1.13 (d, U-6.8 Hz, ZN); 1.16 (d, U-6.4 Hz,

ZN); 1.24 (t, U-2.9 Hz, 6H); 1.29 (d, 9U-5.9 Hz, ZN); 1.53 (m, 4H); 1.78 (m, 1H); 1.84-1.91 (m, 1H); 1.98 (m, 1H); 2.02-2.11 (m, ZN); 2.16 (m, ZN); 2.21 (m, 1H); 2.34 (dd, U-5.9 and 14.2 Hz, 1H); 2.73 (dqv., 9-72 and 7.3 Hz, 1H); 3.08-3.17 (m, ZN); 3.38 (m, 1H); 3.41 (c, ZN); 3.44 (c, ZN); 3.56 (d, 9U-5.9 Hz, 1H); 3.66-3.74 (m, 5H); 3.78 (ddd, U-2.916.0 and 11.6 Hz, 1H); 3.96 (m, 1H); 4.07-4.20 (m, ZN); 4.39 (c, 1H); 4.58 (m, 2H); 4.63 (d, 9-9.3 Hz, 1H); 4.76 (d, 9U-9.8 Hz, 1H); 4.91 (c, 2H); 5.22 (d, U-6.8 Hz, 1H); 7.12 (d,

U-10.3 Hz, 2H); 7.61 (d, 9U-1.5 Hz, 2H); 8.29 (d, U-8.8 Hz, 2H).

Example of obtaining 3.2:

(o) us B on

Iv) p what WHAT tu o t, HOME (o) no o po -o y o o o (c) 7 ra meom on

14.01 g of the compound obtained in preparation example 3.1 is placed in 140 ml of THF, 34.8 ml of 1N HCl solution is added, and stirring is continued for 24 hours at room temperature. The reaction mixture is poured into 200 ml of OSM and washed with 100 ml of water and then with 100 ml of a saturated aqueous solution of sodium bicarbonate. The aqueous phases are extracted with 200 mL of OSM, and the organic phases are combined, dried over Mag 5 O 5 , filtered and then evaporated to dryness in vacuo.

11.48 g of the expected product are obtained.

MS: method a

Tg retention time (min) - 1.19; |M--Ma|": t/2 1040; IM-NANSOONI: t/ 1062.

NMR NMR (400 MHz, m.h., OM5O-av): 0.80 (d, 9U-6.8 Hz, ЗН); 0.95 (m, 15Н); 1.03-1.17 (m, 12H); 1.23 (s, ЗН); 1.30 (d, 9U-5.9 Hz, ЗН); 1.45 (m, 1Н); 1.52 (s, ЗН); 1 .78-1.89 (m, 2H); 1.90-2.24 (m, 8H); 2.37 (dd, 9U-5.1 and 13.9 Hz, 1H); 2.79 (m , 2H); 2.91 (m, 1H); 3.03 (ddd, U-2.7 16.81 9.5 Hz, 1H); 3.13 (sq., U-6.7 Hz, 1H ); 3.32 (masked m, 1H); 3.37 (s, ЗН); 3.45 (s, ЗН); 3.52 (m, 2Н); 3.63-3.72 (m,

ZN); 3.80 (c, ZN); 3.92 (t, U-3.9 Hz, 1H); 4.00 (ddd, U-3,216.1 and 11.7 Hz, 1H); 4.08 (m, 1H); 4.15 (m, 1H); 4.34 (c, 1H); 4.45 (d, 9-81 Hz, 1H); 4.63 (d, 9U-9.8 Hz, 1H); 4.68 (d, 9-42 Gu, 1H); 4.76 (d, 9U-9.5

Hz, 1H); 4.83 (d, 9-71 Hz, 1H); 4.98 (dd, U-5.1 19.0 Hz, 1H); 5.43 (d, 9U-3.9 Hz, 1H).

Example of derivation 3.3: (9)

NU Z ON o, 2 schu o-/ o More o .

Opych o pz in Ge. (9) (c) with Y

Note that 11.4 g of the compound obtained in Preparation Example 3.2 is placed in 114 ml of pyridine, and then 7.4 ml of acetic anhydride is added. The reaction mixture is stirred at room temperature for 24 hours. The pyridine is evaporated in vacuo, and 200 ml is added to the crude reaction mixture

OSM The resulting mixture is washed with 150 ml of 1 N HCl solution, and then with 150 ml of water. The aqueous phases are extracted twice with 200 ml of OSM, and the organic phases are combined, dried over Mag50O»4, filtered and then evaporated to dryness in vacuo. 12.2 g of the compound are obtained, the resulting product is purified using Megsk column chromatography (400 g of silicon dioxide 15-40 μm), eluting with a mixture of 45/55 EOAc/heptane. 8.6 g of the expected product is isolated.

MS: method a

Holding time Tut (min) - 1.29;

IM-ANI": volume 2 1102; (IM-NANSOONI: volume 1146.

Koo) I"H NMR (400 MHz, m.ch., OM5O-av): 0.81 (d, 9U-7.3 Hz, ЗН); 0.95 (m, 15Н); 1.06 (m , 6H); 1.11 (d, 3-6.6 Hz, ZN); 1.20 (d, 9-61 Hz, ZN); 1.24 (s, ZN); 1.29 (d, 9U -3.9 Hz, ZN); 1.41-1.54 (m, 4H); 1.77-1.91 (m, 2H); 1.96-2.09 (m, TON); 2, 11-2.23 (m, 4H); 2.36 (m, 1H); 2.79 (m, 1H); 3.02 (m, 2H); 3.13 (m, 1H); 3.35 (m, 1H); 3.38 (s, ЗН); 3.41 (s, ЗН); 3.52 (d, 9-71 Hz, 1Н); 3.64-3.73 (m, 2Н) ; 3.74-3.83 (m, 5H); 3.86 (width, 1H); 4.06-4.14 (m, 2H); 4.33-4.40 (m, 2H) ; 4.52 (d, U-8.1 Hz, 1H); 4.65 (d, U-9.8 Hz,

1H); 4.76 (m, 2H); 4.97 (dd, U-5.31 8.9 Hz, 1H); 5.02 (d, 9-61 Hz, 1H).

Example of obtaining 3.4 0)

Ge) - 7 x I xx k - o-- te x Her g; ; r | /

Re Ken, what is it?

AT sho - o Ge) | ry o to o o she o i - og o o o - , o - S o t -00o- / / o vet Mom o ot Meomi. 9-4 (3.4.a) (3.4.5) 4 g of the compound obtained in preparation example 3.3 is placed in 190 ml in an argon atmosphere

OSM, and add 4.12 ml of pyridine. The resulting solution is cooled to -202С, followed by the addition of one portion of 0.8 ml of diphosgene, and stirring is continued at -2026 for 3 hours. Add 0.443 g of 4-dimethylaminopyridine, maintaining the temperature at -2020.

Then the resulting mixture is left to warm to room temperature, and stirring is continued for 20 hours. OSM is evaporated in vacuo, and the crude reaction product is placed in 150 ml Es and stirred for 1 hour at room temperature. The resulting precipitate is filtered off and washed with 80 ml of E(Ac. The resulting filtrate is evaporated to dryness in a vacuum, 4.7 g of the expected compounds (structures 3.4.a and 3.4.5) are obtained in the form of a mixture, and the resulting mixture is used without treatment in the next stage

MS: method a

Retention time 3.4.a: Tg (min) - 1.1 MANI": 1251; 3.4.r: Tg (min) - 1.3 |(Me-Ma|): 1187.

Example of obtaining 3.5: and about Uk ov

In her and t, tet y- - shk In No m - o EM g t, m z. av On VYM same now a iz ra y Y au o t o oto A AH u str shchi d y, i o -v- sv, s mem on no no (3.5) a) Condensation of amine A. 0.64 g of the obtained the mixture of compounds obtained in preparation example 3.4 is dissolved in 16 ml

DMF, followed by the addition of 401 mg of M-(2-amino-2-methyl|propyl)-5-nitro-1H-pyrazole-4-sulfonamide dihydrochloride (obtained by the method disclosed in the international patent application

UMO 2009/29439 JSC), and 374 μl of TEA. The resulting mixture was stirred for 4 days at room temperature, and then 75 ml of EIAs was added. The resulting mixture is washed with 50 ml of water and then with 50 ml of a saturated aqueous solution of MaSi. The organic phase is dried over Mo5O, filtered and concentrated under reduced pressure. 0.7 g of the compound is obtained; the obtained product is purified using chromatography on a column with silica gel (MegsK, 30 g of silicon dioxide 15-40 μm), eluting with a mixture of 60/40 heptane/w(Ac. 147 mg of the expected compound are obtained.

Zo p) Removal of protective groups 140 mg of the compound obtained in the previous stage is placed in 3 ml of Meon. Add 70 mg of KgSO3 to the resulting solution. The resulting mixture is stirred for 24 hours at room temperature. Then add 15 ml of EIOAc. The resulting mixture is washed with 10 ml of water and then with 10 ml of a saturated aqueous solution of the mass. The organic phase is dried over Md5O»4, filtered and then evaporated to dryness under vacuum. 0.114 g of the expected product is obtained.

MS: method of r

Ec: t/: 1137 (main peak)

IN NMR (500 MHz, m.h., OM5O-av): 0.79 (d, 9U-6.8 Hz, ZN); 0.93 (m, 9H); 1.01 (d, 9U-6.8 Hz, ZN); 1.10 (m, 18H); 1.17 (m, 9H); 1.64 (c, ZN); 1.80 (m, 5H); 1.99 (m, 4H); 2.13 (m, ZN); 2.65 (m, 1H); 2.82 (m, 2H); 2.96 (m, 5H); 3.30 (masked m, 1H); 3.37 (c, ZN); 3.40 (d, U-9.8 Hz, 1H); 3.46 (c, ZN); 3.51 (m, 1H); 3.60 (m, 2H); 3.67 (m, 2H); 3.78 (m, 1H); 3.80 (c, ZN); 3.85 (m, 1H); 4.08 (width, 1H); 4.36 (m, 2H); 4.44 (d, 9-8.3 Hz, 1H); 4.56 (m, 2H); 4.80 (d, U-6.4 Hz, 1H); 4.99 (width, U-2.0 Hz, 1H); 5.09 (d, U-3.9 Hz, 1H); 6.33 (c, 1H); 6.86 (m, 1H); 8.07 (width, 1H); 14.52 (m, 1H).

Example of obtaining 4: i b AT i lugu hu o o Vi A ry o

Bad and always NI ss zh tu r o oi U oi y to za u" in -fo- - / ot, meom on no no: a) Condensation of amine In 0.64 g of the obtained mixture of compounds obtained in preparation example 3.4, place in 15 ml

DMF. Add 462 mg of M-(2-amino-2-propylmethyl)-2-nitrobenzenesulfonamide hydrochloride (obtained by the method disclosed in Teigapeagop I etsege, 2009, my. 50, 28, pp. 4050-4053) and then add 249 μl of TEA. The resulting mixture is stirred for 3 days at room temperature, and then 75 ml of EIAs are added. The resulting mixture is washed with 50 ml of water and then with 50 ml of a saturated aqueous solution of the mass. The organic phase is dried over Moa5ox, filtered and concentrated under reduced pressure. 0.57 g of the compound is obtained, the resulting product is purified using chromatography on silica gel (30 g of silicon dioxide 15-40 μm), eluting with a mixture of 55/45 heptane/E(OAc). 0.25 g of the expected compound is obtained.

Jur) Removal of protective groups 0.24 g of the compound obtained in the previous stage is placed in 4 ml of Meon. 119 mg of potassium carbonate is added to the obtained solution. The resulting suspension is stirred at room temperature for 24 hours. Add 20 ml of EIOAcS, and the resulting mixture is washed with 10 ml of water and then with 20 ml of a saturated aqueous solution of the mass. The organic phase is dried over Md5O", filtered and concentrated under reduced pressure. 0.197 g of the expected product is obtained.

MS: method of r

From EBzh: t/2 1147 (main peak)

IN NMR (500 MHz, m.h., OM5O-av): 0.79 (d, 9U-6.8 Hz, ZN); 0.90-0.95 (m, 9H); 1.01 (d, 9-68 Hz,

ZN); 1.04-1.14 (m, 18H); 1.15-1.20 (m, 9H); 1.64 (c, ZN); 1.67-1.88 (m, 5H); 1.92-2.05 (m, 4H); 2.09-2.18 (m, ZN); 2.65 (m, 1H); 2.81 (t, U-9.0 Hz, 1H); 2.89-3.12 (m, 6H); 3.31 (partially masked m, 1H); 3.37 (c, ZN); 3.40 (d, 9U-9.5 Hz, 1H); 3.45 (c, ZN); 3.51 (m, 1H); 3.59-3.63 (m, 2H); 3.65-3.71 (m, 2H); 3.78 (m, 1H); 3.80 (c, ZN); 3.85 (dd, 94.7 16.5 Hz, 1H); 4.07 (width, 1H); 4.36 (d, 9U-6.5 Hz, 1H); 4.38 (d, U-8.9 Hz, 1H); 4.43 (d, 9U-7.9 Hz, 1H); 4.52-4.61 (m, 2H); 4.83 (d, 9-71 Hz, 1H); 4.99 (width d, 9-2.9 Hz, 1H); 5.11 (width d, U-4.7 Hz, 1H); 6.32 (width, 1H); 7.77-8.05 (m, 5H).

Example of obtaining 5: put Ya bubu tt no z y 1 Ge) t 23 y 1 o -00- o m ve -00- s m no 0 on not M on no: no": o X t, Tl - ,

Up to 400 mg of sequanamycin (A), 180 mg of (H)-5-(4-(aminooxy)methyl)-1H-1,2,3-triazol-1-ylylmethyl)-3-(3-fluorophenyl)oxazolidine-2 -onu (obtained by the method disclosed in Chotsigpa! oi

Saitbopnuagaie Spetivigu, 2006, mine. 25, pp. 407-425) add 10 ml of MeonN. The resulting solution is stirred for 5 hours at room temperature. Add 20 ml of OSM. The resulting mixture is washed with 20 ml of 1 M NO and then with 20 ml of water. The organic phase is dried over Mod5O, filtered through a sintered glass funnel and then evaporated to dryness. The obtained product is purified using chromatography on a column with silica gel (MegsK, 15-40 μm, 20 g), eluting with a mixture of 95/5 OSM/Meon. 205 mg of the expected compound are isolated.

MS: method of r

E5-: |IM-NANOS»NI: t/2 1296.

I"H NMR (400 MHz, m.h., OM5O-av): 0.81 (d, U-6.8 Hz, ZN); 0.96 (d, 9U-6.4 Hz, 9H); 1.00 (m, 6H); 1.07 (d, 9U-7.3 Hz, ЗН); 1.08-1.13 (m, 9H); 1.17 (m, 6H); 1.24 (c, ZN); 1.46 (m, 1H); 1.69-1.75 (m, 2H); 1.79-1.91 (m, 2H); 1.95-2.20 (m , 7H); 2.73 (m, 1H); 2.81 (m, 1H); 2.89-2.97 (m, 2H); 3.03 (m, 1H); 3.19 (width sq., uU-6.8 Hz, 1H); 3.27-3.38 (partially masked m, 2H); 3.37 (s, ЗН); 3.45 (s, ЗН); 3.52 ( m, 1H); 3.60 (width, 1H); 3.62-3.68 (m, 2H); 3.72 (m, 1H); 3.76-3.85 (m, 2H) ; 3.86-3.94 (m, 2H); 4.26 (t, 3-9.3 Hz, 1H); 4.38-4.46 (m, ЗН); 4.50 (s, 1H ); 4.72 (d, 9U-8.3 Hz, 1H); 4.78 (d, 9U-8.6 Hz, 1H); 4.82 (m,

ZN); 4.89 (latitude, U-3.8 Hz, 1H); 5.10 (c, 2H); 5.12-5.20 (m, 2H); 6.97 (dt, 9U-2.21 8.4 Hz, 1H); 7.27 (width d, U-8.4 Hz, 1H); 7.37-7.51 (m, 2H); 8.22 (c, 1H).

Example 1: Compound 1

Compound 1-a: (28, 35, 48, 5, 75, 95, 105, 118, 125, 138)-7-hydroxy-2-(1--(28, ZB, 48, 58, 6A)-5 -hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|Iuxysupropan-2-yl)-10--(25, ZA, bA)-3-hydroxy-4-(methoxyimino)-6 -methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12(((25, 5A, 7H)-2,4,5 -trimethyl-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl-3-methylbutanoate.

Compound 1: (28, 35, 48, 5B, 75, 95, 105, 118, 125, 138)-7-hydroxy-2-(1--(28, ZB, 48, 58, 6A)-5 -hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|Iuxysupropan-2-yl)-10--(25, ZA, bA)-3-hydroxy-4-(methoxyimino)-6 -methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-((25, 55, 7H)-2,4,5 -trimethyl|-1,4-oxazepan-7-yl|oxyoxacyclotetradecan-4-yl 3-methylbutanoate.

NU tone х Й и о протр Me au, schi Me on that - mem on that iya x MmeOM on ta y 1r K

From g of the compound of the preparation example 1 is placed in 68 ml of MeOHonH. The reaction mixture is cooled in an ice bath to a temperature of 4 "С, then a solution of 3.23 g of sodium periodate in 68 ml of water is added dropwise. The resulting mixture is stirred for 6 hours at room temperature.

The medium is saturated with Mass and filtered, and the resulting filtrate is extracted with OSM (3 x 200 ml). The organic phases are combined, washed with a saturated aqueous solution of Masi, dried over

Maz5och", filtered and finally concentrated under reduced pressure. The obtained oily residue is dissolved in an argon atmosphere in 680 ml Meon. The pH value is adjusted to 7 by adding acetic acid, followed by the addition of 2 M methylamine dissolved in 12.1 ml of THF. pH is maintained at 7 using acetic acid. After stirring for 30 minutes at room temperature, 0.95 g of MavNzoM was added in one portion, and the resulting mixture was stirred for another 16 hours at room temperature. The reaction mixture is filtered and washed with Meon. The obtained filtrate is concentrated under reduced pressure and placed in 600 ml of OSM. The resulting mixture is washed with a saturated aqueous solution of the mass (3 x 60 ml). The organic phase is dried over M9505, filtered and then evaporated to dryness under vacuum. 3.5 g of products are purified using chromatographic processing with a Megsk cartridge (150 g of silicon dioxide 15-40 μm), performing a gradient elution with a mixture from 1000 to 9010 OSM/Meon.

530 mg of diastereoisomer 1-a, 380 mg of diastereoisomer 1-65 and 661 mg of a mixture of two isomers are obtained.

Compound 1-a:

MS: method of r

Tg retention time (min) - 1.26; |MANI": t/2 989; (M-NANSO»NI: n/2 1033 (main peak).

NMR NMR (500 MHz, m.h., OM5O-av): 0.79 (d, U-6.8 Hz, ZN); 0.89-1.01 (m, 15Н); 1.03 (d, 9U-6.8 Hz,

ZN); 1.05-1.10 (m, 9H); 1.11 (d, 9U-6.1 Hz, ZN); 1.13 (d, 9-61 Hz, ZN); 1.24 (c, ZN); 1.48 (dd, U-11.4 and

14.7 Hz, 1N); 1.70-2.08 (m, 8H); 2.10-2.22 (m, ZN); 2.18 (sh.s., ZN); 2.36 (m, 1H); 2.57 (m, 1H); 2.70 (d, U-13.6 Hz, 1H); 2.75 (m, 1H); 2.83 (dd, 9U22.9116.6 Hz, 1H); 2.92 (dd, U-2.718.0 Hu, 1H); 3.03 (m, 1H); 3.12 (sq., U-6.8 Hz, 1H); 3.30 (partially masked m, 1H); 3.38 (c, ZN); 3.45 (c, ZN); 3.52 (m, 1H); 3.58-3.72 (m, 4H); 3.80 (c, ZN); 3.89 (m, 2H); 4.26 (m, 1H); 4.31 (c, 1H); 4.45 (d, 9-8.0 Hz, 1H); 4.65 (latitude, U-9.8 Hz, 1H); 4.70 (d, 9-46 Hz, 1H); 4.74 (d, 9U-9.6 Hz, 1H); 4.86 (d, 9U-7.1 Hz, 1H); 4.93 (dd, 9-31 119.5 Hz, 1H); 5.33 (d, U-4.6 Hz, 1H).

Compound 1:

MS: method of r

Retention time Tg (min) - 1.26: |IM-NANSO»NI: t/: 1033 (main peak).

NMR NMR (500 MHz, m.h., OM5O-av): 0.82 (d, 9U-6.8 Hz, ЗН); 0.91-1.32 (m, З6Н); 1.44 -1.51 (m, 1H); 1.80-1.87 (m, 1H); 1.96-2.37 (m, 10H); 2.76-2.80 (m, 2H); 2 ... 3.07 (m, 2H); 3.12-3.18 (m, 1H); 3.28 (d, 9U-13.7 Hz, 1H); 3.31-3.36 (m, 1H) ; 3.40 (s, ЗН); 3.48 (s, ЗН); 3.51-3.58 (m, 2Н); 3.64-3.70 (m, 2Н); 3.82 (s , ZN); 3.86-3.90 (m, 1H); 3.94-4.02 (m, 2H); 4.31-4.37 (m, 1H); 4.47 (d, 9 -7.9 Hz, 1H); 4.66-4.77 (m, ЗН); 5.12 (dd, U-5.68 and 8.9 Gu, 1H).

Example 2: Compound 2 (28, 35, 48, 5, 75, 95, 105, 118, 125, 138)-2-(1-МК2В8, ЗА, 48, 58, 6НА)-5-hydroxy-3,4 - dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-(25, ZA, /6B8)-3-hydroxy-4-(methoxyimino)-b-methyltetrahydro-2H-pyran -2-yl|oxy)-3,5,7,9,11,13-hexamethyl-6,14-dioxo-7-(C2-(pyridin-4-yl)ethylcarbamoyloxy)-12-((25, 55 , 78)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxidoxacyclotetradecan-4-yl-3-methylbutanoate; /Tx still in Her. Poison: oh, 0, I sha pen

I'm about it and about the goal. he

Stage 2.1 o Yi goon u -on hu pong gu her 9 and 7 o, | e Shsh «ya aty and TU 007 pi z vi ) Shche) i shchi z Sh i yi I yam Y Ye 9 no x z 9 - o /-a y-- vo p what my o 7 - o Z my on hi MeoM 0-4 - : what

(2.1.6) 660 mg of the mixture of diastereoisomers obtained in example 1 is placed in 14.7 ml of pyridine.

Add 631 μl of acetic anhydride. After stirring for 24 hours at room temperature, 189 μl of acetic anhydride are added, and stirring is continued at room temperature for 24 hours. The resulting solution is concentrated in vacuo, and the residue is placed in 200 ml of OCM. The resulting mixture is washed with a solution of NCI (3x5 ml) and then

With a saturated aqueous solution of sodium bicarbonate (2x5 ml) and finally, a saturated aqueous solution of the mass (3x5 ml). The organic phase is dried over Md5O, filtered, and then evaporated to dryness under vacuum. 756 mg of crude product is obtained, the resulting product is purified using chromatographic treatment with a MegoeK cartridge (15-40 μm silica) using a gradient elution with a mixture from 100/0 to 95/75 OSM/MeonH. 287 mg of diastereoisomer 2.1.a and 266 mg of diastereoisomer 2.1.0 are obtained.

Compound 2.1. and:

MS: method of r

Holding time Tut (min) - 1.46; |MeANI": 1073

NMR NMR (500 MHz, m.h., OM5O-av): 0.79 (s, ЗН); 0.91 (m, 6Н); 0.97 (m, 9Н); 1.02 (d , 9-66 Hz,

ZN); 1.07 (m, 12Н); 1.19 (d, 9-61 Gu, ZN); 1.24 (c, ZN); 1.49 (dd, 9U-11.7 114.5 Hz, 1H); 1.82 (m, 4H); 1.98 (m, 4H); 2.05 (c, ZN); 2.08 (c, ZN); 2.16 (m, ZN); 2.20 (c, ZN); 2.44 (dd, 9-9.9 and 14.4 Hz, 1H); 2.64

(m, 1H); 2.74 (m, 2H); 3.03 (m, 2H); 3.12 (sq., 9U-6.7 Hz, 1H); 3.35 (dd, U-4.911 10.1 Hz, 1H); 3.39 (c,

ZN); 3.41 (c, ZN); 3.55 (d, U-8.0 Hz, 1H); 3.67 (m, 2H); 3.79 (m, 2H); 3.78 (c, ZN); 3.86 (t, 9U-2.7 Gu, 1H); 4.14 (m, 1H); 4.31 (c, 1H); 4.37 (dd, 9U-2,519.9 Hz, 1H); 4.52 (d, 9U-8.0 Hz, 1H); 4.65 (d, 929.8 Hz, 1H); 4.76 (d, 929.5 Hz, 1H); 4.79 (d, U-6.8 Hz, 1H); 4.88 (dd, 9U-3.4 and 8.6 Hz, 1H); 5.01 (d, 9-68 Hz, 1N).

Compound 2.1.6r:

MS: method of r

Holding time Tut (min) - 1.46; |MaANI": 1073

IN NMR (500 MHz, m.h., ip OM5ZO-de-TEAzhAsOb): 0.82 (d, U-6.8 Hz, ZN); 0.95 (m, 15Н); 1.06 (m, 9H); 1.20 (m, 6H); 1.25 (c, ZN); 1.30 (d, 9U-6.9 Hz, ZN); 1.48 (m, 1H); 1.84 (m, 1H); 1.94-2.36 (m, 1OH); 2.08 (c, 6H); 2.75 (m, 1H); 2.76 (c, ZN); 3.06 (m, ZN); 3.15 (sq., U-6.5 Hz, 1H); 3.20 (d, 9U-13.7 Hz, 1H); 3.37 (dd, 9U-4.7 19.7 Hz, 1H); 3.40 (c, ZN); 3.43 (c, ZN); 3.54 (m, 1H); 3.60 (m, 1H); 3.68-3.77 (m, 2H); 3.81 (m, 1H); 3.79 (c, ZN); 3.87 (t, 9U-2.4 Hz, 1H); 3.91 (m, 1H); 4.26 (m, 1H); 4.38 (dd, U-2.4 19.9 Hu, 1H); 4.54 (d, 9U-8.0 Hz, 1H); 4.67 (d, 9U-9.5 Hz, 1H); 4.72 (m, 2H); 5.04 (d, U-6.6 Hz, 1H); 5.09 (dd, 925.118.9 Hz, 1H).

Stage 2.2:

I o o Z u t M mulut their o that . g z oi cho . 8o8- i meogi o i -o0- ; o o -- and what - mes 9-4 (hl) And 50 mg of diastereoisomer 2.1.p from the previous stage are placed in an atmosphere of argon in 2 ml of pSM and 65 μl of pyridine are added. The colorless solution is cooled to -102C. Then 10 μl of trichloromethylchloroformate is added, stirring is continued at -102C for 3 hours, and then 5.7 mg (46.67 μmol) of 4-dimethylaminopyridine is added. The resulting mixture is allowed to warm to room temperature, and then stirring is continued for 20 hours.

The resulting mixture is concentrated in vacuo, the residue is placed in 5 ml of EOAc, and the resulting insoluble material is filtered off and washed with 2 ml of EOAc. The resulting filtrate is concentrated in a vacuum. 55 mg of the obtained compound is dissolved in 2 ml of DMF. Then 53.4 mg of 4-(2-aminoethyl)pyridine is added and the resulting mixture is stirred for 48 hours at room temperature. The medium is poured onto the ice/water mixture. The resulting mixture is filtered under vacuum, and then the resulting precipitate is dried under vacuum. 34 mg of the expected product is obtained.

MS: method of r

Z Retention time Tut (min) - 1.16 Eb-: |MA2NIgt/7 611 (main peak); E5-: IM-NANSO2NI: t/2 1265 (main peak)

IN NMR (500 MHz, m.h., OM5O-av): 0.79 (d, U-6.9 Hz, ZN); 0.89-1.11 (m, ZON); 1.17 (m, ZN); 1.64-2.18 (m, 12Н); 1.67 (c, ZN); 2.07 (c, ZN); 2.08 (c, ZN); 2.27 (c, ZN); 2.44 (d, 9-13.2 Hz, 1H); 2.55 (masked m, 1H); 2.70 (m, ZN); 2.85 (m, 1H); 3.02 (m, 5H); 3.35 (masked m, 1H); 3.38 (c, ZN); 3.41 (c, ZN); 3.67 (m, ZN); 3.80 (m, 2H); 3.78 (c, ZN); 3.86 (c, 1H); 4.14 (m, 1H); 4.37 (dd, U-2.21 9.9

Gu, 1H); 4.52 (d, 9U-8.0 Hz, 1H); 4.57 (d, 9U-9.6 Hz, 1H); 4.64 (d, 9U-9.3 Hz, 1H); 4.75 (d, 9-6.6 Hz, 1H); 4.96 (m, 1H); 5.01 (d, U-6.6 Hz, 1H); 6.89 (width t, U-5.4 Gu, 1H); 7.18-7.23 (m, 2H); 8.43 (d, 9-5.5 Gu, 2H).

Stage 2.3:

M /-k g; ох - г -- / о у /й о, ,К-

Kch rem n Y -i m o, o ; ra ck o shi t i ra I S what Y gentlemen,

And in | 97. about | | ry I. sq Mo 7

Ky I ch non y Y 1 x. 32.5 mg of the product obtained at the previous stage is placed in 2 ml of Men with 11 mg K»COz.

After stirring for 1 hour and 30 minutes at room temperature, 20 ml of EtOAc was added to the reaction medium. The resulting mixture is washed with 20 ml of a saturated aqueous solution of Masi. After phase separation by precipitation, the organic phase is dried over Mo5O, filtered and then evaporated to dryness under vacuum. 24 mg of the expected compound are obtained.

MS: method of r

Tg retention time (min) - 0.97; |MA2NI2: 569 (main peak); (M-NANSOSZ2NI-: t/2 1181.

IN NMR (500 MHz, m.ch., OM5O-av): 0.78 (d, 9-6.9 Hz, ZN); 0.96-1.15 (m, ZZN); 1.64-1.87 (m, 6H); 1.92-2.19 (m, 9H); 2.25 (c, ZN); 2.42 (d, 9U-13.4 Hz, 1H); 2.55 (masked m, 1H); 2.70 (m, ZN); 2.85 (m, 2H); 2.92 (dd, 9U-2.31 and 8.1 Hz, 1H); 3.01 (m, 2H); 3.12 (m, 2H); 3.30 (masked m, 1H); 3.37 (c,

ZN); 3.45 (c, ZN); 3.52 (m, 1H); 3.61 (m, 2H); 3.68 (width, 1H); 3.80 (m, 4H); 3.97 (m, 2H); 4.28 (m, 1H); 4.44 (d, 9-8.0 Hz, 1H); 4.53-4.65 (m, 2H); 4.69 (d, U-4.7 Hz, 1H); 4.86 (d, 9-71 Hz, 1H); 4.99 (m, 1H); 5.38 (d, U-4.7 Hz, 1H); 6.89 (m, 1H); 7.23 (d, 9U-5.2 Hz, 2H); 8.43 (d, 9U-5.5 Hz, 2H).

Example 3: Compound C (28, 35, 48, 5B, 75, 95, 105, 118, 125, 138)-7-((dimethylcarbamoyl)oxy|-2-(1--(28, ZE, 48,

BV, 6B)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy)upropan-2-yl)-10-Ш(25, ЗВ, bА)-3-hydroxy -4-(Methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-H(25, 5B, 7B8)-2,4,5-trimethyld|-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl-3-methylbutanoate. oh, / ! 9 m x A and x / U, | zt-io

I. ha 07 then no! Ho -0o- ry

M. / meomM ON

Stage 3.1 (c) h o o m t He on r i M lo i still dry tea

M. AT, -4 o (c) u o -i o o T Ko) o, y | in o. | Mo -what0- -o U-o must with-o . -k. / meom oh ShK r, my o

G. Y

150 mg of compound 2.1.a, obtained in stage 2.1 of example 2, is placed in 9 ml of OSM and 210 μl of pyridine in a 30 ml round-bottom flask, in an argon atmosphere. The colorless solution is cooled to -102C. Then add 30 μl of trichloromethyl chloroformate and continue stirring for 3 hours at -102C, followed by the addition of 17 mg of 4-dimethylaminopyridine dissolved in 2 ml of OSM. The resulting mixture is left to warm to room temperature, and stirring is continued for 20 hours. The resulting mixture is concentrated in vacuo, the residue is placed in 4 ml of DMF, and then dimethylamine hydrochloride (173 mg) is added and dissolved in DMF (2 ml) and TEA (0.3 ml). The reaction mixture is stirred for 3 hours at room temperature. The resulting mixture is poured into an ice/water mixture, and the resulting precipitate is filtered off under vacuum. 146 mg of product is isolated, the resulting product is purified using chromatographic treatment with a MegoK cartridge (5 g of silicon dioxide 15-40 μm), eluting with a mixture of 95/5 OSM/Meon. 93 mg of the expected compound are obtained.

MS: method of r

Tg retention time (min) - 1.33; MANI": 1144

IN NMR (500 MHz, m.h., OM5O-av): 0.79 (d, 9U-6.9 Hz, ZN); 0.92 (m, 6H); 0.96 (d, U-6.6Hz, 6H); 1.05 (m, 18H); 1.17-1.19 (m, ZN); 1.69-2.03 (m, 9H); 1.71 (c, ZN); 2.05 (c, ZN); 2.08 (c, ZN); 2.13 (m,

ZN); 2.21 (c, ZN); 2.44-2.49 (masked m, 1H); 2.72 (m, 6H); 2.84 (sh.s., ZN); 3.03 (m, ZN); 3.33 (masked, 1H); 3.39 (c, ZN); 3.42 (c, ZN); 3.65 (m, ZN); 3.77 (c, ZN); 3.80 (m, 1H); 3.86 (t, U-2.6

Hz, 1H); 3.89 (d, 9U-4.3 Hz, 1H); 4.10 (m, 1H); 4.37 (dd, 9U-2.51 9.9 Hz, 1H); 4.52 (d, 9U-8.0 Hz, 1H); 4.59 (d, 9U-10.1 Hz, 1H); 4.69 (d, 9U-9.6 Hz, 1H); 4.73 (d, 9U-7.3 Hz, 1H); 4.83 (dd, U-3.61 and 7.9 Hz, 1H); 5.00 (d, 9-7.3 Hz, 1H).

Stage 3.2: o (o) 6 U and o x Y / x M

KO -243 x s x . that Mon --Shzhie | In chno "6) tat

I What Gu, t There are still them -06o- o In o -0o- o

ШК мес. 90 mg of the product obtained at the previous stage are placed in 5.5 ml of Meon and 32.6 mg of K»COz.

After stirring for 1 hour and 30 minutes at room temperature, 50 ml of EtOAc was added to the reaction medium. The resulting mixture is washed with 20 ml of a saturated aqueous solution of Masi. After phase separation by precipitation, the organic phase is dried over Mo5O, filtered and then evaporated to dryness under vacuum. 50 mg of the expected compound are obtained.

MS: method of r

Z Holding time Tut (min) - 1.12; |Ma-NI": 1060.

IN NMR (500 MHz, m.h., OM5O-av): 0.78 (d, 9U-6.9 Hz, ZN); 0.92 (m, 6H); 0.96 (d, 9U-6.6 Hz, 6H); 1.01-1.14 (m, 21Н); 1.70-2.06 (m, 9H); 1.71 (c, ZN); 2.09-2.17 (m, ZN); 2.19 (c, ZN); 2.38 (dd, 9-94 and 14.0 Hz, 1H); 2.59 (m, 1H); 2.79 (m, 9H); 2.92 (dd, U-2.6 and 8.0 Hz, 1H); 3.02 (m, 2H); 3.30 (masked m, 1H); 3.38 (c, ZN); 3.46 (c, ZN); 3.51 (m, 1H); 3.63 (dd, 9U-4.4 19.6 Hz, 1H); 3.67 (width, 1H); 3.71 (d, 9-6.9 Hz, 1H); 3.77 (d, 9U-5.4 Gu, 1H); 3.83 (m, 4H); 3.89 (t, 9U-4.9 Gu, 1H); 4.21 (m, 1H); 4.45 (d, 9U-7.9 Hz, 1H); 4.62 (m, ZN); 4.88 (m, 2H); 5.24 (d, U-4.6 Hz, 1H).

Example 4: Compound 4 (28, 35, 48, 5, 75, 95, 105, 118, 125, 138)-2-(1-МК2В8, ЗА, 48, 58, 6НА)-5-hydroxy-3,4 - dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-(25, ZA, /6B8)-3-hydroxy-4-(methoxyimino)-b-methyltetrahydro-2H-pyran -2-yl|oxy)-3,5,7,9,11,13-hexamethyl-7-(2-methyl(|-1-4(5-nitro-1H-pyrazol-4-yl)usulfonyl|iamino )propan-2-ylcarbamoyl|oxy)-6,14-dioxo-12-1(25,7c)-2,4,5-trimethyl|-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl- 3-methylbutanoate o ish shk o U v o. And in bo SCHO le vot" o lu her oo Hu vi y 2 no oo t Ge shu - t Z no" - o, -0ЙБ10- ;,' 520 / НН z o no-4 / MeoM on oo g moyu on not : X 102 mg of the product obtained in Preparation Example 3 is placed in 2 ml of Meon.The resulting solution is cooled to 09C, and a solution of 86 mg of sodium metaperiodate in water (2 ml) is added.

The reaction mixture was stirred using a magnetic stirrer at room temperature for 5 hours. Add 15 ml of OSM, and the resulting mixture is washed with 10 ml of water and then with 10 ml of a saturated aqueous solution of MaSi. The organic phase is dried over Moe5O", filtered and concentrated under reduced pressure. 86 mg of the obtained product is dissolved in Men (10 ml), the resulting solution is cooled to 02C and then methylamine (84 μl of a 2M solution in THF) and acetic acid (9.7 μl) are added. After stirring for 10 minutes at 0 "C, add 13.34 mg

MavNzoM. The reaction mixture was stirred for 1 hour at 09C and then allowed to warm to room temperature, and stirring was continued for 20 hours.

Add 20 ml of OSM, and the resulting mixture is washed with 15 ml of a saturated aqueous solution of ManHsSoz and then with 15 ml of saturated aqueous mass solutions. The organic phase is dried over Md5O", filtered and concentrated under reduced pressure. 0.12 g of the obtained product is purified using preparative LC/MS, performing gradient elution with a mixture of 15/85 to 95/5 acetonitrile/water containing 0.195 TEA. Fractions with mass from 1278 to 1281 are isolated. The pH of the isolated phases is adjusted to 8 using a saturated aqueous solution of ManHsSoOz and then extracted with 50 ml of EIHUAc. The organic phase is dried over Mo5O, filtered and then evaporated to dryness under vacuum. 38 mg of the expected product is obtained.

MS: method of r

Holding time Here (min) - 1.06: |MaMa|": 1278

IN NMR (500 MHz, m.h., OM5O-av): 70/30 mixture of diastereoisomers, 0.78 (d, U-6.8 Hz, ZN); 0.91 (d, U-6.8 Hz, ZN); 0.95 (m, 9H); 1.02-1.16 (m, 27Н); 1.68 (sh.s., ZN); 1.71-1.90 (m, 4H); 1.93-2.21 (m, 8H); 2.36 (width, 2.1H); 2.46 (width, 0.9H); 2.61 (m, 1H); 2.69-3.06 (m, 9H); 3.30 (masked m, 1H); 3.38 (c, ZN); 3.46 (c, ZN); 3.49-3.64 (m, 2.3H); 3.67 (t, U-2.6 Hz, 1H); 3.72 (m, 1H); 3.78-3.91 (m, 2.7H); 3.80 (c, ZN); 4.30 (m, 1H); 4.45 (d, 9U-7.9 Hz, 1H); 4.57-4.67 (m, ZN); 4.83 (d, U-6.8 Hz, 1H); 4.96 (dd, 9U-3,019.2 Hz, 0.7H); 5.04 (dd, 9-4.8 and 8.6 Hz, 0.3Н); 5.26 (width, 0.7N); 5.36 (width, 0.3H); 6.32 (width, 1H); 6.70 t, 1H); 7.89-7.93 (m, 1H).

Example 5: Compound 5

From Compound 5a: (28, 35, 48, 5, 75, 95, 105, 118, 125, 138)-2-(1--(28, ZB, 48, 58, 6B8)-5-hydroxy- 3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-((25, ZA, 6B8)-3-hydroxy-4-(methoxyimino)-b-methyltetrahydro- 2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-7-(2-methyl-1-(2-nitrophenyl)sulfonyl|amino)propan-2-ylcarbamoyl| oxy)-6,14-dioxo-12-(25, 58, 78)-2,4,5-trimethyl|-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl-3-methylbutanoate.

Compound 5-р: (28, 35, 48, 5, 75, 95, 105, 118, 125, 138)-2-(1--(28, ZB, 48, 58, 6B8)-5-hydroxy-3 ,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-((25, ZA, 6B8)-3-hydroxy-4-(methoxyimino)-b-methyltetrahydro-2H -pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-7-(2-methyl-1--(2-nitrophenyl)sulfonyl|amino)propane-2-ylcarbamoyl|oxy )-6,14-dioxo-12-4(25, 55, 78)-2,4,5-trimethyl|-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl 3-methylbutanoate. syu si s i sii pa nya hui so OV mm mu E 5 ra u

I'm a magician still no go o o o i o (c) What) as 7 n Z SHHI on 9 and yo, (5.a) (5.5)

A solution of 99 mg of the product obtained in Preparation Example 4 and 2 ml of MeOH is cooled to 02Сb. Then a solution of 83 mg of MaЙО4 in 2 ml of water is added dropwise. After 15 minutes at 0", the resulting mixture is left to warm to room temperature, and stirring is continued for 3 hours. The reaction mixture is poured into 20 ml of OSM. The resulting mixture is washed with 10 ml of water, the phases are separated by precipitation and then washed again with 10 ml of a saturated aqueous solution of the mass. The organic phase is dried over Md5O»4, filtered and then evaporated to dryness. To a solution of 95 mg of the compound obtained in this way in 8 ml of MeOH, 110 μl of a 2M solution of methylamine in THF, 13.9 μl of ASON, and finally 16.67 mg of Mavnzsm, in in the specified order. The resulting mixture is stirred for 20 hours at room temperature. 20 ml of OSM is added, and the resulting mixture is washed with a saturated aqueous solution

ManHsCOz and then an aqueous solution of Massi. Aqueous phases are extracted by OCM. The organic phases are combined, dried over Mo95O, filtered and then evaporated to dryness. 85 mg of the obtained product is combined with another portion of 68 mg of the product obtained in the previous reaction under the conditions described above. The resulting mixture is purified using chromatography on silica gel (10 g of silicon dioxide 15-40 μm), eluting with a solvent of 94.5/5.65 OSM/MeOn.

49 mg of diastereoisomer 5-a and 30 mg of isomer 5-5 are obtained.

Compound 5a:

MS: method of r

Holding time Tut (min) - 1.16; MANI": 1288

IN NMR (500 MHz, m.h., OM5O-av): 0.78 (d, 9U-6.8 Hz, ZN); 0.90 (d, 9U-6.8 Hz, ZN); 0.92-0.97 (m, 9H); 1.00-1.17 (m, 27Н); 1.62-1.70 (m, 4H); 1.71-1.85 (m, 4H); 1.89-2.08 (m, 4H); 2.13 (c, ZN); 2.19 (c,

ZN); 2.39 (dd, 9U-9.7 and 14.2 Hz, 1H); 2.59 (m, 1H); 2.74 (m, 2H); 2.83-3.11 (m, 6H); 3.28 (masked m, TN); 3.38 (c, ZN); 3.46 (c, ZN); 3.52 (quintet, y-6.2 Hz, 1H); 3.62 (dd, U-4.4 and 9.68 Hz, 1H); 3.68 (m, 2H); 3.76 (d, 9U-4.5 Hz, 1H); 3.82 (m, 5H); 4.26 (quintet, uU-7.2 Hz, 1H); 4.45 (d, 9-7.9 Hz, 1H); 4.59 (d, 929.9 Hz, 1TN); 4.68 (m, 2H); 4.83 (d, 9-71 Hz, 1H); 4.91 (dd, U-2,819.2 Hz, 1H); 5.23 (d, 94.4 Hz, 1H); 6.28 (c, 1H); 7.91 (m, 5H).

Compound 5:

MS: method of r

Holding time Tut (min) - 1.16; MANI": 1288

Zo IN NMR (500 MHz, m.h., OM5O-av): 0.78 (d, 9U-6.8 Hz, ZN); 0.90 (d, 9-7.0 Hz, ZN); 0.95 (d, U-6.7

Hz, 9H); 1.00 (d, 9U-6.7 Hz, ZN); 1.05 (m, 9H); 1.09 (d, U-6.2 Hz, ZN); 1.13 (m, 9H); 1.24 (c, ZN); 1.66 (c, ZN); 1.78 (m, 4H); 1.99 (m, 4H); 2.13 (m, 4H); 2.25 (c, ZN); 2.42 (d, 9U-13.0 Hz, 1H); 2.53 (m, 1H); 2.74 (quintet, U-7.3 Gu, 1H); 2.87 (m, 4H); 2.98 (sq., U-6.4 Hz, 1H); 3.07 (m, 2H); 3.32 (masked m, 1H); 3.37 (c, ZN); 3.46 (c, ZN); 3.52 (m, 1H); 3.62 (m, 2H); 3.67 (t, 9U-2.5 Hz, 1H); 3.80 (m, 4H); 3.88 (m, 2H); 4.29 (quintet, uU-7.8 Hz, 1H); 4.44 (d, 9U-7.9 Hz, 1H); 4.58 (d, 9U-9.3 Hz, 1H); 4.63 (d, 9U-9.4 Gu, 1H); 4.72 (d, 94.5 Hz, 1H); 4.83 (d, 927.2 Hz, 1H); 5.00 (dd, U-4.51 9.1 Hz, 1H); 5.35 (d, U-4.5 Hz, 1H); 6.27 (width, 1H); 7.74-8.05 (m, 5H).

Example 6: Compound 6 (28, 35, 48, 58, 75, 95, 105, 118, 125, 138)-7-(benzylcarbamoyl)oxy|-12-(25,7H8)-4-(2-fluoroethyl) -2,5-dimethyl/|-1,4-oxazepan-7-yl|oxy)-2-(1-((28, ZA, 48, 5, 6H)-5-hydroxy-3,4-dimethoxy- b-methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-(25, ZA, /6B8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2- yl|oxy)-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl-3-methylbutanoate. (9) o M hui o

Oh, and xx od no: oh to so -- . 0.5 g of the compound obtained in preparation example 2 is placed in 10 ml of Meon. The resulting solution is cooled to 02C. Then a solution of 0.475 mg of sodium metaperiodate in 10 ml of water is quickly added dropwise. After 15 minutes at 02C, the resulting mixture is allowed to warm to room temperature, and stirring is continued for 5 hours. The medium is saturated with Masi (3 g) and transferred to OSM (40 ml). The precipitate is filtered and washed with a saturated aqueous solution of Masi. The aqueous phase is extracted by OCM. The organic phases are combined, dried over Mo95O, filtered and then evaporated to dryness under vacuum. 443 mg of the expected product are obtained. 100 mg of the specified compound is dissolved in 2.2 ml of MeoOonH, followed by the addition, in the specified order, of 25 μl of TEA, 22 mg of 2-fluoroethylamine hydrochloride, 12.7 μl of acetic acid and, finally, 16.86 mg of MavHzsM. The medium is stirred for 20 hours at room temperature. Add 20 ml of OSM, and the resulting mixture is washed with a saturated aqueous solution of sodium bicarbonate and then with an aqueous solution of Masi. Aqueous phases are extracted by OCM.

The organic phases are combined, dried over NaCl5O, filtered and then evaporated to dryness. 92 g of the obtained product is purified using chromatographic treatment on silica gel (5 g of silicon dioxide 15-40 μm), eluting with a mixture of 97/3 UOSM/Meon. The expected product is obtained in the form of a mixture of diastereoisomers.

MS: method of r

Tg retention time (min) - 1.28; |IM-NANSO»NI: t/ 1198.

NMR NMR (500 MHz, m.ch., OM5O-av): 70/30 mixture of diastereoisomers 0.78 (d, 9U-6.8 Hz, ZN); 0.91 (d, U-6.9 Hz, ZN); 0.94 (d, U-7.3 Hz, ZN); 0.98 (dd, 9U-1.6 1 6.6 Hz, 6H); 1.01-1.16 (m , 21H); 1.60-2.22 (m, 15H); 2.52 (masked m, 1H); 2.59 (d, U-5.0 Hz, 1H); 2.68-3.08 (m, 9H); 3.28 (masked m, 1H); 3.38 (s, 3H); 3.46 (s, 3H); 3.52 (m, 1H); 3.64 (m, 2H ); 3.72-3.93 (m, 7H); 4.10 (d, 9U-6.0 Hz, 2H); 4.24 (m, 1H); 4.41 (m, ЗН); 4 .56-4.72 (m, ZN); 4.83 (d, 9-7.1 Hz, 1H); 4.88 (m, 0.7H); 4.99 (dd, 9U-4.0 9.1 Hz, 0.3H); 5.13 (d, U-4.6 Hz, 0.7H); 5.31 (d, U-4.6 Hz, 0.3H); 7.28 ( m, 5H).

Example 7: Compound 7

Compound 7-a: (28, 35, 48, 5, 75, 95, 105, 118, 125, 138)-7-(benzylcarbamoyl)oxy|-2-(1- (en, ze, 4H, 5, 6H) )-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl|oxy)propan-2-yl)-10-((25, ZA, bA)-3-hydroxy-4- (Methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-6b,14-dioxo-12-1(25, BV, 78)- 2,4,5-trimethyl/|-1,4-oxazepan-7-yl|oxidoxacyclotetradecan-4-yl-3-methylbutanoate.

Compound 7-0: (28, 35, 48, 5, 75, 95, 105, 118, 125, 138)-7-(benzylcarbamoyl)oxy|-2-(1- (en, ze, 4H, 5, 6H) )-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl|oxy)propane-2-

Zoyl)-10-((25, ZA, bA)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11, 13-hexamethyl-6b,14-dioxo-12-1(25, 55, 78)-2,4,5-trimethyl|-1,4-oxazepan-7-yl|oxyoxacyclotetradecan-1,4-yl 3-methylbutanoate . (e) o u U o y I p Ge! pa, Shchi Go) pai o cho i o o po » ov o -606- - o 5 i-o I (r Mem zn i MeOM On

IY Be (7.g) (1.6) 0.68 g of the compound obtained in preparation example 2 is placed in THF (7 ml). The resulting solution is cooled to 02C. Then a solution of sodium metaperiodate in 7 ml of water is quickly added.

After 15 minutes at 02C, the resulting mixture is allowed to warm to room temperature, and stirring is continued for two hours. The resulting precipitate is filtered off and washed with 7 ml of THF. Add a 2N solution of methylamine in 1.21 ml of THF and then add 139.04 μl of acetic acid. After stirring for 5 minutes at room temperature, add 199.63 mg of MavNzoM. The resulting suspension is stirred at room temperature for 20 hours. The resulting precipitate is filtered and washed with 50 ml of OSM. The filtrate is washed with 30 ml of a saturated aqueous solution of MaHSOO and then with 30 ml of a saturated aqueous solution of Masi. Aqueous phases are extracted with 50 ml of UOSM. The organic phases are combined, dried over

Ma5O", filtered and then evaporated to dryness in a vacuum. The obtained product is purified using chromatographic treatment with a MegoK cartridge (50 g of silicon dioxide 15-40 μm), eluting with a mixture of 94/6 SNCl3/MeH. 320 mg of the expected compound 7-a, 77 mg of another diastereoisomer 7-B and 147 mg of a mixture of diastereoisomers are obtained.

Compound 7a:

MS: method of r

Tg retention time (min) - 1.31; |IM-NANSO»NI: t/; 1166 (main peak).

IN NMR (500 MGu, m.h., OM5O-dv-СО3С000): 0.81 (d, 9U-6.9 Hz, ZN); 0.93 (d, 9U-6.8 Hz, ZN); 0.95-1.02 (m, 9H); 1.05-1.17 (m, 15Н); 1.24 (d, 9U-6.0 Hz, ZN); 1.30 (d, 9U-6.6 Hz, ZN); 1.74 (m, 7H); 2.04 (m, ZN); 2.18 (m, 5H); 2.78 (c, ZN); 2.79 (m, 1H); 2.89 (d, 9U-14.8 Hz, 1H); 2.93 (dd, 9U-2,518.0 Hz, 1H); 3.03 (m, 2H); 3.13 (m, 1H); 3.35 (m, 2H); 3.40 (c, ZN); 3.45 (m, 1H); 3.48 (c, ZN); 3.51 (m, 2H); 3.68 (m, 2H); 3.82 (c, ZN); 3.87 (m, 2H); 3.94 (d, 9U-4.9 Hz, 1H); 4.13 (d, 9U-5.7 Hz, 2H); 4.45 (m, 2H); 4.62 (m, ZN); 5.12 (dd, U-4.51 and 8.4 Hz, 1H); 7.28 (m, 6H).

Compound 7:

MS: method of r

Tg retention time (min) - 1.32; |IM-NANSO»NI: t/; 1166 (main peak).

IN NMR (500 MHz, m.h., OM5ZO-dve--СозС000): 0.82 (d, U-6.9 Hz, ZN); 0.94 (d, U-6.8 Hz, ZN); 1.02 (m, 9H); 1.08 (m, 6H); 1.14 (m, 9H); 1.22 (d, 9-61 Hz, ZN); 1.34 (d, U-6.8 Hz, ZN); 1.75 (c, ZN); 1.82 (m, ZN); 1.90-1.95 (masked m, 1H); 1.99 (m, 2H); 2.09 (m, 1H); 2.19 (m, ZN); 2.35 (m, 2H); 15. 2.69 (m, 1H); 2.79 (c, ZN); 2.96 (m, 2H); 3.04 (m, 2H); 3.15 (dd, U-9.6 and 13.6 Hz, 1H); 3.23 (d, 9U-13.6

Hz, 1TN); 3.32 (dd, 9-48 and 9.7 Hz, 1H); 3.40 (c, ZN); 3.48 (c, ZN); 3.53 (m, 2H); 3.66 (m, 2H); 3.70 (t,

U-1.0 Hz, 1H); 3.80 (m, 4H); 3.94 (d, U-5.2 Hz, 1H); 4.06 (width, 1H); 4.14 (m, 2H); 4.38 (m, 1H); 4.47 (d, 9-7.9 Hz, 1H); 4.56 (m, ZN); 5.15 (m, 1H); 7.21-7.33 (m, 6H).

An alternative method of obtaining the compound 7-а и у с 2-0 о,

There are prunennitO "zh Ge she ) I Ge) that

BUT. Ge) -0o- 3-o i / 5 MmeomM on ra (ta) 0.2 ml of CHO", 12 mg of compound 8-a of example 8, 108 μl of 0.1 M formic acid and 3 μl of formaldehyde are added together with stirring, in an argon atmosphere, and the resulting mixture is heated for 30 minutes at 502C. The reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with SOHC. The organic phase is dried over Moaz5ox, filtered and then evaporated to dryness in vacuo. The resulting residue is purified using chromatography on silica gel (2.5 g 15-40 μm ION) using gradient elution with a mixture of 95/5 to 90/10 CHCl3/MeOH. 6.2 mg of expected products are obtained.

Another alternative method of obtaining compound 7-a 3 in 5-9 o, o - - stump

More; o no" Y o b t -o0 / y z MmeoM on ra (7.d)

Stage 1 m o ; and in o, 2 and in o what pipnnnnnn O

Po o o to i o b v6- z-o / o

That meom 9-4 r mak

AND

1.35 g of compound 1-a of example 1 and 1.11 g of M,M'-carbonylimidazole are placed in 8 ml of cyclohexane. The resulting mixture is heated at 1002C for 35 minutes using microwave radiation. The heterogeneous medium is placed in 60 ml of OSM and washed with 40 ml of water and then with 40 ml of saturated Masi solution. Aqueous phases are extracted again with 60 ml of OSM. The organic phases are combined, dried over Md5O»54, filtered and then evaporated to dryness under vacuum. 1.7 g of the expected compound are obtained.

MS: method e

Time of retention of Ttg (min) - 3.67; (MANI: 1271

Stage 2 bull

Y E I-i du what o y y o o en o o "o

BUT. Ge) because it's 5 o'clock

Add 1.7 g of the compound obtained in stage 1 to 17 ml of THF. Add 6.84 ml of 1 M NH.

The resulting mixture is stirred for 3 hours at room temperature. Add 50 ml of OSM, and the resulting mixture is washed with a saturated solution of Manso»z (20 ml) and then with a saturated solution of the mass (20 ml). Aqueous phases are extracted again with 50 ml of OSM. The organic phases are combined, dried over

Oil, filtered and then evaporated to dryness under vacuum. 1.48 g of the expected product is isolated.

MS: method e

Holding time Here (min) - 3.41; |MaANI": 1083

Stage Z (9) 9 My KU

Kk p, DISHOT e) and non (c) zo -o5- and o o /

With meoMm on ra (7.c) 1 of the product obtained above is placed in DMF (10 ml). Add benzylamine (305.54 μl) and 1,68-diazabicyclo|5.4.Fundec-7-ene (168.87 μl). The resulting mixture is stirred at room temperature for 24 hours. The resulting mixture is extracted with 60 ml of E(OAc), washed with 30 ml of water and then with 30 ml of a saturated solution of MacCl. The aqueous phases are extracted again with 60 ml of EOAc.

The organic phases are combined, dried over Ma5O, filtered and then evaporated to dryness under vacuum.

1.1 g of yellow oil is obtained. The obtained product is purified using chromatographic treatment with a MegeK cartridge (50 g 15-40 μl 5ION), eluting with a mixture of 98/2

ECOAS/TEA. 400 mg of the expected compound are obtained.

Example 8: Compound 8

Compound 8-a: (28, 35, 48, 58, 75, 95, 105, 118, 125, 138)-7-(benzylcarbamoyl)oxy|-12-((25,

BA, 7H)-2,5-dimethyl|-1,4-oxazepan-7-yl|oxy)-2-(1-(2H, ZA, 48, 5, 6H)-5-hydroxy-3,4- dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-(25, ZA, /6B8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran- 2-yl|oxy)-3,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl-3-methylbutanoate.

Compound 8-р: (28, 35, 48, 58, 75, 95, 105, 118, 125, 138)-7-(benzylcarbamoyl)oxy|-12-((25, 55, 7B8)-2,5- Dimethyl|-1,4-oxazepan-7-yl|oxy)-2-(1-I(28, ZA, 48, 58, 6H)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H- pyran-2-yl|oxypropan-2-yl)-10-(25, ZA, /6B8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3 ,5,7,9,11,13-hexamethyl-6,14-dioxooxacyclotetradecan-4-yl-3-methylbutanoate. о о О У о ух но". о чо BUT о то - о : о -5- : о и-о / 3 - о I

MmeoM on meoM on

K. Io (v.a) (8.6) d- z- o N o M same OO pu

Co o la pectin Cl o t, drinking part of the day - о-- и о -о - и о у, о и у о 2 meoM on mmeOoM on

Kk Io (v.a) (8.6)

Step 8.1: (9) 5 g of 1 mL of toluene, 0.2 g of the product obtained in Preparation Example 1, and 196 mg of M,M'-carbonyldiimidazole is placed in an argon atmosphere. The reaction mixture is heated for 3 hours at 802C and then concentrated in vacuo. OSM is added and the resulting mixture is washed with a saturated aqueous Masi solution. The organic phase is dried over Md5O»5, filtered and then evaporated to dryness under vacuum. The residue is purified using chromatography (10 g of 15-40 μm silica), using gradient elution with a mixture of 98/2 to 95/5 osM/Meon. 112 mg of the expected compound are obtained.

MS: method of r

Holding time Tut (min) - 1.63; |MaANI": 1300

Stage 8.2:

o In KZ where 1 o, sly, - and o t, panny tu o How

BUT eh o -6o6- -o 4 o MeOM on eye:

With ml of THF, 240 mg of the macrolide obtained in step 8.1, and 369 μl of 1 M HCl are mixed together under an argon atmosphere. The pale yellow homogenous medium is stirred overnight at room temperature. A new portion of 369 μl of 1 M NSII is added and stirring is continued for 24 hours. The reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate. The resulting mixture is extracted with E(Ac. The organic phase is dried over M9504, filtered and then evaporated to dryness in vacuo. 181 mg of the resulting residue is purified using chromatography (10 g of 15-40 μm silica) using a gradient elution with a mixture from 50/50 to 70 /30 EtOAc/heptane 87 mg of the expected compound are obtained.

MS: method of r

Tg retention time (min) - 1.56; |IM-NANSO»NI: t/; 1156 (main peak).

Stage 8.3: g, in the south;

Because) oh

He) p Z - ., ennnnnnitO a o i i) I no". o b F- Z (o) i o MmeOM on oko i 10 ml of DMF, 1 g of the compound obtained in stage 8.2, 188 μl of 1,8- diazabicyclo|5.4.O)undec-7-ene and 138 μl of benzylamine are mixed together under an argon atmosphere. The resulting homogeneous medium is stirred overnight at room temperature. 20 g of ice is added to the reaction mixture, and the resulting mixture is extracted with 3x20 ml of EIOAc. The organic phases are combined and washed with 20 ml of saturated aqueous solution of the mass, and the organic phase was dried over Md 5 O", filtered and then evaporated to dryness in vacuo. 975 mg of the residue was purified using chromatography (50 g, 15-40 μm silica), eluting with a mixture of 7/3 EIOAc /heptane 490 mg of the expected compound are obtained.

MS: method of r

Tg retention time (min) - 1.68; |M-NANSO»NI": t/; 1195 (main peak).

IN NMR (500 MHz, m.ch., OM5O-av): 0.79 (d, 9-6.9 Hz, ZN); 0.88-1.01 (m, 12Н); 1.05 (m, 6H); 1.11 (m, 6H); 1.14 (d, U-6.0 Hz, ZN); 1.30 (d, 9-5.5 Hz, ZN); 1.52 (c, ZN); 1.67-1.86 (m, 4H); 1.71 (c, ZN); 1.94-2.10 (m, 4H); 2.15 (m, 4H); 2.36 (dd, U-5.1 and 13.6 Hz, 1H); 2.77 (m, 2H); 2.92 (dd, U-2,518.0 Hz, 1H); 3.01 (m, 2H); 3.27-3.32 (masked m, 1H); 3.37 (c, ZN); 3.45 (c, ZN); 3.52 (m, 2H); 3.61-3.68 (m, 2H); 3.80 (c, ZN); 3.84 (d, 9U-6.9 Hz, 1H); 3.95 (m, 2H); 4.13 (m, ZN); 4.45 (d, 9U-8.0 Hz, 1H); 4.55 (d, 9U-9.9 Hz, 1H); 4.65 (m, 2H); 4.87 (d, 9U-7.1 Hz, 1H); 4.99 (dd, U-5.4 and 8.4 Hz, 1H); 5.43 (m, 1H);

Zo 1.26 (m, 5H); 7.38 (width t, U-6.0 Hz, 1H).

Stage 8.4 cha M, mu nd

B te) o, o shu with t

NO Ge) - o i / no meoM on noi: 55 ml of MeonH, 300 mg of the macrolide obtained at the previous stage, and 108 mg of K»COz are mixed together in an argon atmosphere. The reaction mixture was stirred for 24 hours at room temperature, followed by the addition of an additional portion of 72 mg of KgSO3. The reaction mixture is stirred for another 24 hours, and then 30 ml of a saturated aqueous solution of Masi is added.

The resulting mixture is extracted with EtOAc (3x100 ml). The organic phase is isolated after phase separation, dried over Mu9BzO»x, filtered and then evaporated to dryness. 300 mg of the obtained residue is purified using chromatography (30 g, 15-40 μm silica), eluting with a mixture of 7/3 EIOAc/heptane. 265 mg of the expected product are obtained.

Stage 8.5: 9) Fr

Ge) J o n bu U ney 9 WHAT 9, KK

Ky o te, TT Ky o "ba, ladies eh, there is ov | o ov , o i-o; ;i-

MmeOM on meomMm on (o (o (v.g) (8.5) 3.5 ml of THF and 340 mg of the compound obtained at the previous stage are mixed together in an argon atmosphere. The resulting solution is cooled to 02С, then an aqueous solution of 325 mg of sodium metaperiodate in 3.5 ml of water Stirring is continued at 020 for 10 minutes and the resulting mixture is then allowed to warm to room temperature.

After stirring for 5 hours and 30 minutes, the resulting precipitate is filtered off and washed with 4 ml of THF. Add 64.8 mg of MNASI to the obtained filtrate, then, after stirring for 5 minutes at room temperature, add 95 mg of Mavnzcm.

The reaction mixture was stirred at room temperature for 20 hours. The resulting precipitate is filtered and washed with OSM. The filtrate is washed with a saturated solution of sodium bicarbonate and then with an aqueous solution of Masi. Aqueous phases are extracted by OCM. The organic phases are combined, dried over Md5O, filtered and then evaporated to dryness under vacuum. 278 mg of the residue is purified by chromatography on silica gel (20 g, 15-40 μm 5IOH) using gradient elution with a mixture of 98/2 to 95/5 SNCI3/MeonN. 120 mg of diastereoisomer 8-a and 14 mg of diastereoisomer 8-r are obtained.

Compound 8a:

MS: method of r

Tg retention time (min) - 1.3; |IM-NANSO»NI: t/ 1152 (main peak).

NMR NMR (500 MHz, m.h., OM5O-av): 0.78 (d, U-6.6 Hz, ZN); 0.91 (d, 9U-6.9 Hz, ZN); 0.95 (d, 9-71

From Hz, ZN); 0.99 (d, 9U-6.6 Hz, 6H); 1.03-1.12 (m, 21Н); 1.75 (m, 8H); 1.99 (m, 4H); 2.15 (m, ZN); 2.50 (masked m, 1H); 2.68-2.94 (m, 5H); 3.01 (m, 2H); 3.29 (masked m, 1H); 3.38 (c, ZN); 3.45 (s,

ZN); 3.52 (m, 1H); 3.61-3.90 (m, 6H); 3.80 (c, ZN); 4.10 (m, ZN); 4.45 (d, 9-7.7 Hz, 1H); 4.62 (m, ZN); 4.86 (d, 9-71 Hz, 1H); 4.95 (m, 1H); 5.26 (d, U-4.4 Hz, 2H); 7.20-7.32 (m, 5H); 7.36 (t, U-6.0 Hz, 1H).

Compound 8:

MS: method of r

Tg retention time (min) - 1.12; IM-NANSO»NI: t/ 1152 (main peak).

IN NMR (500 MHz, m.h., OM5O-av): 0.78 (d, 9U-6.9 Hz, ZN); 0.91 (d, U-6.6 Hz, ZN); 0.98 (m, 9H);

1.03-1.16 (m, 21Н); 1.69-2.20 (m, 12Н); 1.72 (c, ZN); 2.71 (m, ZN); 2.92 (m, 2H); 3.01 (m, ZN); 3.10 (m, 1H); 3.34 (masked m, 1H); 3.38 (c, ZN); 3.45 (c, ZN); 3.52 (m, 1H); 3.63 (dd, 9U-4.51 9.7 Hz, 1H); 3.67 (width, 1H); 3.71-3.81 (m, ZN); 3.79 (c, ZN); 3.87 (t, 9U-4.7 Hz, 1H); 4.09 (m, ZN); 4.45 (d, 9U-8.0

Hz, 1H); 4.60 (m, ZN); 4.83 (d, 9U-6.9 Hz, 1H); 5.01 (m, 1H); 5.14 (d, 9U-3.6 Hz, 1H); 7.20-7.35 (m, 6H).

Table 1

Structures and analyzes of compounds obtained by one of the methods disclosed in examples 1-8 above and 9-11 below

Gender Chemical structure of І5М

RUGUR

(c) more "o zhan! (M-N-NSO»NI-: t/y 1196 . 1.02 vy o (main peak)

No" Y y o still n u ,; o y - Su annnio) Y Ш 2 y 1.01 IM ninSO NI i t/2 1196 o (; (main peak) no» n ,Y, (c) (c) XX 14 o and 1.04 (M-n-NSO»NI:: t/2 1224 o (main peak) no : and more, More

look at

Us and t e baths IM-NANSO»NI-: t/y 1224 12 BI r u 103 (main peak) that ve u on ,; c) not o still shvaeshati IM-NANSO»NI-: t/2 1180 13 . 1.04 o (main peak) no" is

От 0 у он о 7 /

Continuation of table 1 I uv. aries and 14 t or menya 1.19 IMANIkk: 1225 7 in ron, vk shi | IMANIs: 1253, 15th of the 9th 12125 mixture of isomers

That is "he n he h." where else am I? What is tn 16 tr» or pohyukta 12 IMANIkk: 1251 ke z - i o vch V ' Zh.) Ku

At 2 - another 4 hours on the 17th 1841 M-NeNSO»NI: t/x 1237 tA and t, ' (main peak) -yu -- - with re a-

Go) x Pp Shk ky a

IN

Wow

We are KI

Uudutnya U z vs et i 18 s, nah x ! 1.32 IMANI ks: 1221 pi shk

SU to» rya r i:

FI o anode teach Her. in I and ksmoevyuvtnovouu.

Solution IM-NANSO2NI-: t/2 1240 19 pa Y m 1.36 (main peak)

In hmm - B- and Z -oa in ve b. p pin av a

Continuation of table 1 soya t ya K BU U " a O--n hi ya she kino MYH b on 20 er" y 1.16 IM-ANIk: 1296 eh They - yiv ra -y n- yon yae- bu stu y o with us and 24 va and ! 5 in 117-419 t/2 306 (main peak) - zba ' "7 | a mixture of isomers: i pot m 5 rak 7 shk Ya m ro ya shchi at no shk shk 22 nan | Uvi 1.26 IM-ANIk 1273 - v- i et them, 'she oj o ol Be t -e U zhu di ee ; ii Z bo tia v Koch

U. veto t/z 1251 (main piyu)- 23 | ш 129 251 (osn ) and a mixture of isomers and 1 I he and vomu ay che and not o sche ur» . from the beach

And killed t/2: 207 (main peak); 24 as 1 min 1.2 . p shi a IM-NANSO»NI-: t/ 1257 ri y kh on -- nya yi iya Another 9. koh - 9 zn y - z still as o i Yi he 1 53 IM-NANSO»NI-: t/; 1272 zi ie ША " (main peak) 7 ohm on bony k-ty y

Continuation of table 1 ry shk a. x t bro! etc

With their IM-n2 legs k: 619 (main 26 et r that 1.04 | peak); (M-NANSO2NI-: t/2 and that ha 1280 she yoy a y

And 7 Jan 27 will lose 121 PM-NeNSO NO: pug 1164 ha I shk; (main peak) pe and | min t in 28 houses 1000 TsManik 1225

Shi g t HER h 8 yannia, w NN She ked Zoe

OYASHU Koh on le ny mixture of isomers nov | ha zo zate vrbtnn і09 (Meni 1197 y y ), y en nen ! re ZV M M o more: E more sn

From to fu and 111 (Me: 1211 ni, ! i Av

She and | Wow

You are

Continuation of table 1, September 32, 1117. TsMA-NneNSO»NI-: t/» 1240 «pre x | thread ke ne y and shchi -k Still a vn

PI

- we and at 33 vh sha your to them (mani 1273 fon . Fo0d-yak S: t chen mn v en

ZA ped three nu 11000 Me 1267 at | IMUNI vaye Z stump - I and. І 5.vi mesh х. Tire with M Zhonnnnui uni oku U 1.85 MAN-NSO»NI-: t/y 1192 oku noi -i p kre y "( r. Ky on sho y

Fa pora I (MeNiIe: 1311 36 | ha ce x | letu mixture of isomers still

OK IM-NyaNSONI-: tu 1268 sh i 198 (main peak)

Continuation of table 1 as x- І Ka not /z

ZV de - 1.35 IM-NANSO»NI-: t/ 1254 g t shk ' (main peak) yun ! 4 in o - oi

OM and M on

M (c) g s. eat From number 11. khvo IM-NANSO»NI-: t/ 1272 39 53 - in 1.3 (main peak) i ( in) Ku what

Shi m on o o

IN as cho, pennnnn

Its "about t/2: 265 (main peak); 40 more 1.33 (4). (MAN-NSO»NI-: t/g 1315 - - is a mixture of isomers

M on (c) in- R

Year, sho ha shchi Y, t/z: 250 (main peak); Yes, yes! at 1.29 (4). | (M-NANSO»NI-: t/» 1300 - - o i on mixture of isomers min

AH A I p

Ali 117: i drink); chne t/2: 263 (main peak); 42 e3z| and h 125 CM-nUnSoni-: tu/h 1313 that ts and XX on sha and -i No m: s

AH

In still pi 43 17 g 124 | M-NeNSONI-: t/2 1169 53 Y Y ho ; (main peak) failure (don

In le and in Ei

BA

Continuation of table 1 of the seam 44 x I r | 1 30-1.52 IMAeNICsk: 1226 mixture

R our uz p | yan and pred t/lx isomers: 267 (main peak); 78 pava a 123 Tsm-nUnooin-: tu 1317 and What is 005 place

In M r S a Her and 09 t ey

RO M-NANSONI-: t/2 1295

X se a 46 non/ i Yar? h 129 (main peak) - in no and / | Mon ish y

Khy o what er Ba pe) 47 June r m 1.83 | t/l: 330 (main peak) - because -

And Ge

Year |) zdo M / tk u o, - y

H u TYA M 48 A 1 F | t/2: 258 (main peak); wa tsi ! Me IM-NANSO»NI|-: t/2 1308 -r m E | I vn

I ii SOY and oh,

A oi it 49 in tu » 1.28 IM-NANSO»NI-: t/2 1365 in x a in mae SH

She Ya chi - I t zosh y; i tn 8 i

Continuation of table 1: already ve o

Eyes and

BO Ya ra 115 (9) YMANNSON: pukh 1351 - ve Z MV a 'mixture of isomers see. o, tk t r r / don

I don't know about Z y s x y ty hu t o shcha - shshishe Х Х t/2: 327 (main peak); z I U y : 1.257129 du: 301 (main peak) sha: eto r che: ZY Doc

These are gays

ХА г г я Z les и «7 ki и Z o. sh: her She and ShY 52 ha sr xx | 114 |t/x: 315 (main peak) no x x - ke o i mon do ITh vra cy Go s be x i -ya i y ren vi nn NN schi v 5Z v: NIK Y chi 112 | t/:: 315 (main peak) svnya h vra

In AI

My God y er t IM-NANSO»NI-: t/t 1286 54 In t What 2.20-2.22 | (main peak) -

Who and | In a mixture of isomers -y oo i-sh3p M,

Dung is what it is / ryy what is;

OK and I have 5 years! 106 (mg: 637 (main mass and peak) ve o | U

I am in

Continuation of table 1

M and St IM-N-NSO»NI-: t/2 1222 56 o 2.36-2.39 | (main peak) - her k. M mixture of isomers kr shk ah that t/2: 345 (main peak) - 57 neo fr 2.382 : t. B w mixture of isomers i in t

B ON i Y zu s

Ай 1 ие и | t/2 306 (main peak); 58 Width and 1.21-1.23 | (M-NANSO»NI-: t/2 1330 - pt and a mixture of isomers! 2 Zradoya ye d-ikh that o r» y - shk IM-NANSO2NI-: t/2 1301 her shk SHI and shcha 116 (main peak) av. Ma vy b k. » ie

Y m yar» kuru 118 IM-NANSO2NI-: t/2 1194 m tr ' (main peak) - o tt U a --i ui sia

Goroya so even ha "Zh kh ru Y S yan et vi 3 ut ry pen 4 i 630 (main -i o i ! 5

S Sh K dn t u;

Continuation of table 1

Ya ayu x x- g: eh t-ki 62 oh: HB 142 (Mane 1301 t. Y i | Kha nshikh

By -- 63 AZ 1.08. | t/x: 1035 (main peak) mayor Mon not in u . I. ve vch n 2 M-o tu

I IM2NI2 -k: 666-t/2:248 64 for and her 1.33-1.34 | (main peak) -

Sha o or a mixture of isomers da ni dk zeit t t yat t shk 65 oh pen 113 (Meni 1315 vych n Sho ch ia b, du tu ten

Z r. Kolya g. S. water and st. g. 116 (M-N-NSO»NI-: t/2 1033

Noni! Ua (main peak) - o t M - 3 / Y eat tr her 67 tsoachshnnne 119 TsManie 1235 va: SHE

Shi and | these

Continuation of table 1 x z y ud: t - i shi (M-NYANSO»NI-: t/ 1123 o, ver 1.19-1.20 | (main peak) - also from the same mixture of isomers above

He s A gh s KK to sew 115 IM-ANIk: 1243 ho ! EK where". sb ee S y on 70 un yiy5 (Me 1243

A shen of sleep 7 m Ts Uzi

A. g i Ton alley

NO What -

This is a mixture of isomers

Example 9: Compound 70 (28, 35, 48, 5, 75, 95, 105, 118, 125, 138)-2-((5)-1-((28, ZB, 48, 58, 6H8)-5 -hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl)uoxy)propan-2-yl)-10-(((25, ZA, 6H8)-3-hydroxy-4-(methoxyimino )-b-methyltetrahydro-2H-pyran-2-yl)oxy)-3,5,7,9,11,13-hexamethyl-7-((2-methyl-1- ((phenylsulfonamido)propan-2-ylcarbamoyl )oxy)-6,14-dioxo-12-((25,5B,7B8)-2,4,5-trimethyl-1,4-oxazepan-7-yl)oxy)oxacyclotetradecan-4-yl-3-methylbutanoate . about N shchi Her. pa sl-a o 9) o c) t ; Y tr 007» sht) - pa o o Ko) or -6o- /7 9 ,-y r meom on (70)

Stage 9.1

Eat in; x sheon d i

Another shk sechnanita

Shh! about N

He ate) o o /7 o, t u; m meom tu

From g of compound 1-a, obtained in example 1, is placed in pyridine (30 ml). Add acetic anhydride (2.88 mL). The resulting mixture is stirred at room temperature for 40 hours.

The resulting mixture is concentrated in a vacuum, and extracted 3 times with 60 ml of OSM, washed with 40 ml of 1 M

NOI, then a saturated aqueous solution of Mansoz, and finally, a saturated solution of Masi. The organic phases are combined, dried over Md5O, filtered and then evaporated to dryness. 3.5 g of the expected product in the form of a white powder are obtained.

MS: method e

Holding time Tut (min) - 4.01; |MaANI": 1073

Stage 9.2 shu

M. Z

B N them in ZO oso o, t NKU scha o .. o o What)

NO nya o v v-- t Go) / o Mmeom ON (70)

Stage 9.2.a: 4.2 g of the compound obtained in stage 9.1 is placed in OSM (150 ml). Pyridine (5.43 ml) was added and the resulting mixture was cooled to 02C. Add trichloromethyl chloroformate (diphosgene) (842.40 μl) and stirring is continued for 3 hours at 02C. 4-Dimethylaminopyridine (507.03 mg) was added, then the resulting mixture was allowed to warm to room temperature and stirring was continued overnight. The resulting mixture is evaporated to dryness in a vacuum.

The crude product of the reaction is used without processing in the next stage.

Stage 9.2.r: amine condensation

DMF (70 mL) was added to the crude reaction mixture obtained in the previous step.

A dark brown suspension is obtained. TEA (4.91 mL) was added in one portion, then M-(2-amino-2-methyl|propyl/ubenzenesulfonamide) hydrochloride (2.80 g) was added in one portion.

The reaction mixture was stirred with a magnetic stirrer at room temperature for 24 hours. Add 400 ml of EUAs. The resulting mixture is washed with 200 ml of water and then with 200 ml of a saturated aqueous solution of the mass. The aqueous phases are extracted again with 400 ml of E(OAc). The organic phases are combined, dried over Md5O", filtered through a sintered glass funnel and concentrated under reduced pressure. 8 g of brown oil are isolated.

Stage 9.2.c: removal of protective groups from alcohols

Meon (40 ml) is added to 8 g of the brown oil obtained above. They receive

The solution is yellow-brown in color. Potassium carbonate (1.30 g) is added in one portion. The reaction mixture was stirred with a magnetic stirrer at room temperature for 2 hours and minutes. Add 150 ml of OSM. The resulting mixture is washed with 75 ml of water and then with 75 ml of a saturated aqueous solution of the mass. Aqueous phases are extracted again with 150 ml of OSM. The organic phases are combined and then dried over Md5O» and finally filtered through a sintered glass funnel.

The resulting filtrate is evaporated to dryness, and 3.5 g of yellow-brown foam is isolated.

The resulting product is purified using preparative HPLC under the following conditions:

" Apparatus: Umaieg5 4000 " Stationary phase: Kgoptavii C18 10 μm 300x50 mm "- Mobile phase: B: 70/30 vol./vol. acetonitrile/NgOzh10 mM ammonium acetate solution "Flow rate: 120 ml/min "- UV detection: 210 nm " Cell length: 2.5 mm

After evaporation and lyophilization, we get: 800 mg in the form of a yellow powder, which corresponds to the expected product.

MS: method of r

Holding time Here (min) - 1.15; (MANI: 1243 "H NMR (500M Gu, m.ch., OM5O-av): 0.77 (d, U-6.6 Hz, ЗН); 0.88-0.97 (m, 12Н); 1.00-1.15 (m, 27H); 1.62-1.82 (m, 4H); 1.67 (s, ЗН); 1.90-2.05 (m, 4H); 2, 09-2.20 (m, 4H); 2.19 (s, ZN); 2.39 (dd, 9-9.7 and 13.9 Hu, 1H); 2.59 (m, 1H); 2 ... 1H); 3.30 (m, 1H); 3.37 (s, ЗН); 3.45 (s, ЗН); 3.52 (m, 1Н); 3.59-3.69 (m, ЗН ); 3.76 (width, 3-41 Gu, 1TN); 3.80 (s, ЗН); 3.83 (m, 1Н); 3.88 (t, U-4.8 Hz, 1Н ); 4.28 (m, 1H); 4.45 (d, 9U-8.0 Hz, 1H); 4.59 (d, 9-9.9 Hz, 1H); 4.68 (m, 2H ); 4.87 (d, 9-71 Hz, 1H); 4.91 (dd, 9U-2,619.2 Hz, 1H); 5.27 (d, y-4.8 Hz, 1H); 6, 22 (s, 1H); 7.51 (width t, U-6.6 Hz, 1H); 7.58 (t, 9U-7.5 Hz, 2H); 7.63 (t, 9-7 .5 Hz, 1H); 7.78 (d, 9-7.5 Hz, 2H).

Example 10: Compound 72 (28, 35, 48, 5В, 75, 95, 105, 118, 125, 138)-10-(25, ЗВ, 68)-4-Щ(1-1(58)-3- (3-Fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl|Imethylyl)-1H-1,2,3-triazol-4-yl)methoxy|imino)-3-hydroxy-6-methyltetrahydro -2H-pyran-2-yl|oxy)-7-hydroxy-2-(1-4(28, ZA, 48, 5A, 6H)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H- pyran-2-yl|oxysupropan-2-yl)-3,5,7,9,11,13-hexamethyl-6b,14-dioxo-12-Ch(25,5A,7H)-2,4,5- trimethyl/|-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl-3-methylbutanoate. 7 o tropi ----- ek in tu odi oe- U i -00- cho o y - Ge i no yah On o v 3 -Z oi

Me and that

MME

200 mg of the compound obtained in preparation example 5 is placed in 2 ml of THF, the resulting solution is cooled to 02C, and then 172.51 mg of sodium metaperiodate dissolved in 2 ml of water is added. The resulting mixture is left to warm to room temperature, and stirring

Continue for 4 hours. The precipitate is filtered and washed with 0.5 ml of THF.

400 μl of a 2 M solution of methylamine in THF is added to the obtained filtrate, then 46 μl of acetic acid and finally, 63.5 mg of MavNzSM. The resulting suspension is stirred at room temperature for 18 hours. The obtained suspension is placed in 40 ml of OSM. The resulting mixture is washed with 20 ml of a saturated aqueous solution of MaHSOO and then with 20 ml of a saturated aqueous solution of Masi. The organic phase is dried over Md5O5, filtered and finally concentrated under reduced pressure. The crude mixture is purified using chromatography with a Megsk cartridge (10 g of 15-40 μm silica), eluting with a mixture of 92/8 SNCl3Z/MeOHn.

41 mg of the expected product and 5 mg of another stereoisomer are isolated.

MS: method of r

EB: IM-NANSO»NI: t/ 1293

IN NMR (500 MHz, m.h., OM5O-av): 0.79 (d, 9U-6.8 Hz, ZN); 0.93 (d, 9U-6.8 Hz, 6H); 0.95-1.00 (m, 9H); 1.02 (d, U-6.6 Hz, ZN); 1.05-1.14 (m, 15Н); 1.24 (c, ZN); 1.48 (m, 1H); 1.69-1.80 (m, 2H); 1.83-2.07 (m, 6H); 2.11-2.21 (m, ZN); 2.17 (c, ZN); 2.35 (dd, 9U-9.4 1 14.1 Hz, 1H); 2.56 (m, 1H); 2.69 (d, 912.6 Gu, 1H); 2.75 (m, 1H); 2.83 (dd, 9U-3.0116.5 H, 1H); 2.92 (dd, U-2.61 7.9 Hu, 1H); 3.03 (m, 1H); 3.12 (square meter, U-6.8 Hz, 1H); 3.30 (partially masked m, 1H); 3.38 (c, ZN); 3.45 (c, ZN); 3.52 (m, 1H); 3.59-3.73 (m, 4H); 3.82-3.94 (m, ZN); 4.22-4.28 (m, 2H); 4.31 (c, 1H); 4.45 (d, 9U-7.9 Hz, 1H); 4.66 (d, U-9.7 Hz, 1H); 4.68 (d, U-4.7 Hz, 1H); 4.74 (d, 9U-9.4 Hz, 1H); 4.82 (d, U-5.3 Hz, 2H); 4.86 (d, 9-72

Gu, 1H); 4.91 (dd, 9U-3.1 119.4 Hu, 1H); 5.11 (c, 2H); 5.15 (m, 1H); 5.30 (d, 9-4.7 Hz, 1H); 6.97 (dt, 9-2.318.4 Hz, 1H); 7.27 (dd, 9-1,518.4 Hz, 1H); 7.40-7.47 (m, 2H); 8.21 (c, 1H).

Example 11: Compound 88 (28, 35, 48, 5, 75, 95, 105, 118, 125, 138)-2-((5)-1-((28, ZB, 48, 58, 6H8)-5 -hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl)uoxy)propan-2-yl)-10-(((25, ZA, 6H8)-3-hydroxy-4-(methoxyimino )-b-methyltetrahydro-2H-pyran-2-yl)oxy)-7-(methoxycarbonyl)oxy)-3,5,7,9,11,13-hexamethyl-b,14-dioxo-12-((25 , 78)-2,4,5-trimethyl|-1,4-oxazepan-7-yl)oxy)oxacyclotetradecan-4-yl-3-methylbutanoate. what's wrong - 5 To Heaven (88)

Stage 11.1 o All id 7 o, u, ah o kill i p u y ota fo A- o

556 mg of the mixture of diastereoisomers obtained in Example 1 and 456 mg of M,M'-carbonyldiimidazole are placed in cyclohexane (3.3 ml). The resulting mixture is heated at 1002C for 35 minutes using microwave radiation. The heterogeneous environment is placed in 30 ml

OSM is washed with 20 ml of water and then with 20 ml of saturated Masi solution. Aqueous phases are extracted again with 30 ml of OSM. The organic phases are combined, dried over Mo5O5, filtered and then evaporated to dryness under vacuum. 710 mg of the expected product are obtained.

MS: method a

Time of retention of Ttg (min) - 1.19; (MANI: 1271

IN NMR (m.h., OM5O-4dv)-VhaKeg spectrometer: 0.79 (d, U-6.9 Hz, ZN); 0.85 (d, 9-71 Hz, ZN); 0.90-0.95 (m, 12Н); 1.01 (d, 9U-6.9 Hz, ZN); 1.06-1.14 (m, 9H); 1.17 (d, 9-6.3 Hz, ZN); 1.25 (d, U-6.3

Gu, ZN); 1.75-1.87 (m, ZN); 1.92 (c, ZN); 1.94-2.18 (m, 9H); 2.20 (c, ZN); 2.47 (m, 1H); 2.65-2.81 (m,

ZN); 3.07-3.19 (m, ZN); 3.37 (m, 1H); 3.41 (c, ZN); 3.44 (c, ZN); 3.63-3.78 (m, ZN); 3.72 (c, ZN); 3.93-4.00 (m, 2H); 4.10-4.17 (m, 2H); 4.56-4.64 (m, ZN); 4.69 (d, 9U-9.6 Hz, 1H); 4.84 (m, 1H); 5.00 (d, 9-74

Gu, 1H); 5.24 (d, 9-7.4 Hz, 1H); 7.10 (dd, 950.81 1.6 Hu, 1H); 7.12 (dd, 90.81 1.6 Hu, 1H); 7.15 (width, 1H); 7.46-7.47 (t, 9U-1.6 Hz, 1H); 7.62 (t, 9U-1.6 Hz, 1H); 7.64 (t, U-1.6 Hz, 1H); 8.12 (latitude, 1H); 8.28 (width, 1H); 8.30 (shyr.s, 1H).

Stage 11.2 o same Ka; u ve o, o r -x fa VOSHI is) er she o o cho

BUT about ob ryh / and mem on ry

500 mg of the compound isolated in step 11.1 is placed in THF (5 mL). Add a 1M solution of hydrochloric acid (1.97 ml). The resulting mixture is stirred for 3 hours at room temperature. Add 50 ml of OSM, and the resulting mixture is washed with a saturated solution

Manso:z (20 ml) and then a saturated solution of Masi (20 ml). The aqueous phases are extracted again with 50 ml

OSM The organic phases are combined, dried over Moa50O5, filtered and then evaporated to dryness in vacuo. 420 mg of the expected product is isolated.

MS: method a

Holding time Here (min) - 1.02; |MaNI": 1083

Stage 11.3 o i "Lo o p that U ee p, bennannnshnto tr o o o o na

NOtych o - o - / ro MeoM on (88) 50 mg of the compound obtained in step 11.2 is placed in Men (1 ml). Potassium carbonate (32.22 mg) was added, and the resulting mixture was stirred at room temperature for 4 hours. A ml of OSM is added and the resulting mixture is washed with water and then with a saturated solution of Masi. Aqueous phases are extracted with 15 ml of OSM. The organic phases are combined, dried over Mo5O5, filtered and then evaporated to dryness under vacuum. 57 mg of varnish are obtained, the product obtained is purified using chromatographic treatment with a MegsK cartridge (2.5 g of 15-40 μm 5ION), eluting with a mixture of 97/3 EIOAS/ TEA. A fraction with Ex 0.35/0.45 (central fraction) is isolated, i.e. 14 mg of the expected compound.

MS: method a

Holding time Here (min) - 1.07; MANI": 1047

IN NMR (500 MHz, m.h., OM5O-av): 0.76-0.81 (m, ZN); 0.89-0.94 (m, 6H); 0.96 (d, 9U-6.6 Hz, 6H); 0.99-1.17 (m, 21Н); 1.73-1.82 (m, 6H); 1.85 (m, 1H); 1.91-2.06 (m, 5H); 2.11-2.21 (m, 6H); 2.38 (dd, 914.0, 9.6 Hz, 1H); 2.53-2.66 (m, 1H); 2.66-2.77 (m, 2H); 2.81-2.89 (m, 1H); 2.92 (dd, 9U-7.8, 2.6 Gu, 1H); 2.98-3.06 (m, 2H); 3.27-3.31 (masked m, 1H); 3.38 (c, ZN); 3.45 (c, ZN); 3.48-3.56 (m, 1H); 3.58-3.71 (m, 6H); 3.74-3.78 (m, 1H); 3.80 (c, ZN); 3.82-3.92 (m, 2H); 4.26 (d, 9U-6.3 Gu, 1H); 4.45 (d, 3-8.0 Hz, 1H); 4.59 (d, 9U-10.2 Hz, 1H); 4.63-4.75 (m, 2H); 4.81-4.94 (m, 2H); 5.29-5.34 (m, 1H).

Table 2

Structures and analyzes of compounds obtained by one of the methods disclosed in examples 1-8 above and 9-11 below

Spol Chemical structure of io5M

RUGUR o oi o, tone and lm singing o g go o. . . 78 pa in this ' 1287. | Menik 114855 is a mixture of two isomers

Meo o ze 4 o za

Sl

Continuation of table 2

Her. 74 ml 7 ; 1319 IMANI Kk: 1184.5 mixture shk pu SHCHO on ' isomers 7 07 o. Con 75 on three ovi" Menie 112266 mixture ml 7 Ton ' isomers of me gu ze o Mry y "Z sha: nu (MNK: 1152.6 mixture 78 At ! 1209 | isomers o- ke -y 7 pa y "1 ovvi 0 Menier: 10833 mixture of mo pu ' isomers

Ka m ran o

In / in. She i-i o, i) "ik i (MN k: 1102 mixture 78 0 u 1.04 isomers sb o

Che and him

SI 7 - Y Y

In tone three (Men 1029.6 mixture 73 pi ch i oi Y 1.087 isomers o - o Zo

Continuation of table 2

Her, zey about: ; 1 078 IMANIkK: 1033.5 a mixture of isomers

Her A. o uy ek mo Meni 1178.6 sumi 81 shwa She CHI i t2v MeNIYE 5 mixture

І A isomers se

Her. yati no IMENI": 1095.5 sumi ortho y : 55 mixture 82 vad I re 0.899 | Zomeriv and Ag 97

Us 83 vai s om 1026 Imenie 1083.7 mixture

In | isomers

Ki hu still n yo, o, -k va what tu 114. MNK 1087 mixture of -0 o and o isomers o o "on 7 Ge

See what) 9) Ш c) . H 85 53 h 113. MENIK 1031 mixture of isomers b o. and M o

AND--

Continuation of table 2 (c)

In AJ

/ Fe". ХО ак шк ' 1489 Мени 1190.8 a mixture of yuyu which - in ' isomers - 0. Я о и шк r

Shk o-mM he and. in, about

Y U Ku 87 ki ny 0.63 | (I have 12004

Oh, in the 1st year

Yi ra om "on he yi

It's about me pobzo about, - then Ne) vv about | 107. MayaNik 1047 mixture

But these are isomers. And how did he go?

Go)

PI and at -7

I am holy about that Me 10747 no" about -v

A--0

S in the city

There are 1.017 (m2gnugk 605 mixture . oo sh isomers o o. . ge) -- 0 la ton noboo шШ в! charge 6 zevv Memain 115277 mixture

But o, g "o - o Y o

Chu

- M le on

Continuation of table 2

United Nations: 1116.4 mixture of 92 U t, ii and T272 isomers with Ton utbo o o o nM-57 o y t dichnyu (Manu: 1271 mixture of 93 ii rcho 1716 isomers - 0 - o and he

She

Her. o pe o, ke o Zo still mon . N o SCHE IM-NIk: 1114 mixture of 94 no» id g -9 115 isomers - o. - o /5 i x O-M sn

M / oo o o uv o, - 95 oi i SHI iiy8 Meni 1283 no» vo -o- - z (0) in oh on oo shi; buguls From o. K da sh - i nin IM--NIk: 1283 mixture of ma yak "o 118 isomers -o-: o rol o on ev M ve o te it (MN is 1313 mixture of 97 ii g cho 114 isomers -o- ot o what M on zysh

Continuation of table 2 below; se is about tt 1 tvo Manre 1283 0 Ж, ' IMZHNNIe -- o. N d) (9)

SHCI he : i

More and more x-dv. that M

ASHSH Aa 1049 Megnugya: 582.4 mixture of 17; isomers no" and zo

She | y: those y - me-y oon nsoon

I. uyu r yus o i. and your din (magnug: 596.2 mixture 100 o 1 . ! 1.336 isomers o o - o y M o t u-

Mme- o-m he and un? 9 A - 101 khr 121. TsManiye 1299 mashe -o- - o (o) r oi on

I x Y ; on; / in dsh-o cho; common name: 1283 mixture of 102 isomers of 122 isomers

C o Y - cv)

I (me2nugia: 587.5 mixture 103 I dnry te 1.045 isomers

Continuation of table 2 c uy 7 y Shko shk IM2HnNu2 zh: 604 mixture pi o, p 0.889 isomers ke | with.

S. shk lot (c) o y

And what, V vyky i Her echo IMANITSk: 1279.6 a mixture of 105 of dich o 1205 isomers

M -m dream

Who is 920 o su he V zu

С, ИМеНИк: 1311.6 mixture of 706 о Vi "о 1.234 isomers - и о и о те - у он и в с вв ИMENIK: 1261.6 mixture 107 О осли о 1176 isomers

In ley on

Her 108 shawls 1224 NAMES 1327.6 mixture

I o" isomers of La Ge

Eat

Usui - (Mne: 13276 mixture 109 9, e o 1224 |. . nya isomers o I Go pe "on

Continuation of table 2

Х х Х и 110 пе 1027 Megnugzh: 580.4 a mixture of и и и и isomers р Й with И,

Ge) t» - uko pi moy shchi po otva PMegnugya: 604.2 mixture -o- - | in: ' isomers t pud on «on c) okotu

U A zho 112 and U, sh-- 124 Menie 1284 mixture o rn . ! isomers

S o m o n s / food and r. ne shin (MNK: 1269 a mixture of А m 12 | isomers h v on

OO

(c) et» he seams (M'nNuk 1311 mixture 114 Me m 121 | isomers m ol

How are you?

U. and Ra 115 tires 119 (Meni 1257 - about r

Continuation of table 2 oy 6 5 kutu o ach 1153 | Me2nug: 659.4 mixture of ach o ; isomers no ho Oso N fishti / o

Oh m Her. br more 7 E IMANIK: 1311.8 mixture 117 mg. . 0929 | measured

S "on y gu" in Tovet i (MeNIk 1261.6 mixture of 118 m obo 1.194 isomers -40. . o t

Shk m on o o ukoy above I (Menik 1279.6 mixture 119 o Ty, 1253 isomers -o- and U o t 0-x -k - on o ? / But paste zu y 0" to her n o ol (MNuk: 1297.6 mixture 120 5 that 1.222 isomers - m on chiral chiral

Who am I

Mu o M Her X M zr g (Me 1312.7 sumi ne o o : 77 mixture 121 ai | s 1.169 isomers g o / sh- r o

Well,

Continuation of table 2

She

Х н г-оН 0, - 6). - 122 o ono 0.932 (M'zhnuk 1079.5 mixture of - isomers -o o- J o

Z-o sl b o - I. in U 9, - oi (MeNIk 10946 mixture 123 to, in 7o p 0.975 isomers - 0. - U o (9) dokt y

UF don about, - , her Me) about | (MaeNIk 1057.6 mixture of 124 of three 116 isomers b o Y o

A--o su o-ch on

She

. p chno | I 125 and m 0.823 (M'NIk 1065.6 mixture

But there are many isomers

Se U

M ut on (c) ru -on b, - kh shchey pn o . . in and DI E 1215. MH 1045.7 mixture

Other) isomers - o and Mo 5-o / c) 9, se ditya zno 127 i V Ho i 1197 YIMANIE 1003.5 a mixture of t o that isomers - o and o --o

Is it in

Continuation of table 2

Eat in; SU ie o, -

HB (Me Ne: 1043.8 a mixture of 128 5 o. p. 0.93 isomers of obligatory x on (

She

In gaOH o, - 7 o is still potable, 129 no" and rr p 0.971 (MH is: 1059.7 a mixture of bo | uz isomers

Xiang on

AND

She's going, oh, well. - senntO

DC; (MaeNIk: 1029.5 mixture 130 then 0.852 isomers - 0. and o)

But "he

Heh | sleep and SHI in Shih (MH is: 1150.6 sumi no" yo : 6 mixture

What -o- and o n 0.884 isomers (in what o-m pt

He) no, ton bebtretre (Me 1016.6 mixture 132 po lo 0.886 isomers);

Y u sen o, - i No) shi IM'-NIk: 1107.7 mixture 9) 133 o o Y 1.275 isomers - o. Y o si o on rya /

Continuation of table 2

I as b k- i o) al ta . : 134 from 1! 1224 | 101.7 is a mixture of two isomers. and 79 kA TO about - -m on

Go) b k- y - panashtO ot and IM'-NI Kk: 1045.6 mixture

Te) 1 135 o i r I t isomers in o. and M o --0

And in he ut o -on i wl (Men 1186.5 mixture 186 yun, DI, . ! 1253 isomers bo and | o - o

With nn om he

With / so t u; 2) still ho her g. : dnyny IM'ANIk: 1045.6 mixture 137 sb Y | chi p 1.039 isomers shk She bu A reli on

Yi oo, hon to drink. ooo" o NAME: 1017 .6 mixture 138 g AH SHI v! y 1219 isomers no n Gen meo me 57 ze ku

Using

Compounds corresponding to the general formula (I), which is the object of this invention, were subjected to microbiological studies, which showed their value as therapeutically active substances. More specifically, they have a bacteriostatic and/or bactericidal effect on mycobacteria, especially against strains of Musobasiegisht or Soguperasiegisht, which are particularly susceptible and resistant to first-line antibiotics.

The compounds corresponding to the general formula (I), which is the object of this invention, also have a bacteriostatic and/or bactericidal effect on gram-positive microorganisms, especially on staphylococci and streptococci.

More specifically, the compounds corresponding to the general formula (I), which is the object of this invention, are used for the prevention and/or treatment of bacterial infections caused by mycobacteria and gram-positive microorganisms.

Measurement of the inhibitory activity (IC) of the compounds of this invention against Zigeriosossiv5 rpeitopiae

Materials and methods

As a test, a bioluminescent test is used, the purpose of which is to measure the inhibition of bacterial growth of ZmtsBeriosossi5 rpeshtopiae by quantitative determination of adenosine triphosphate (ATP). More specifically, ATP is the main and mandatory carrier of energy in many reactions of cellular metabolism, which characterizes the living environment.

ATP is quantified at the end of the test using the enzyme luciferase, which produces a measurable amount of light in the presence of ATP and the specific substrate luciferin.

Thus, in the presence of luciferin and luciferase at concentrations that do not reach saturation, the value obtained in relative light units (CI) makes it possible, using calibration, to determine the amount of ATP, and thus calculate the number of living bacteria at the end of the incubation period.

So, the higher the CI value obtained at the end of the test tends to zero, the stronger the product inhibits the overall growth of bacteria.

The obtained results (Table 3) are expressed in ISvo. ISvo corresponds to 80 95 inhibition of bacterial growth 5. rpestopiae compared to the antibiotic vancomycin, for which ISvo is 0.14 µM.

The conducted experiments demonstrated that the compounds of this invention have activity in relation to the inhibition of the growth of 5. rpeshtopiae. IC values are usually between 0.1 and 10 μM, or even between 0.1 and 1 μM.

Measurement of the inhibitory activity of the compounds of this invention against ippirogue

Musobasiegiit shregsiio5iv

In the used IP migo test, it turned out to be possible to identify molecules that have antimicrobial activity against the Musobasiegisht yshregscio5ie Nz7Vu strain. This strain is a bacterium of the category C of biological danger.

Materials and methods

Alamar blue (Aiatag Bichet (MAVA)) is used in the test in question. This

It is a colorimetric test that allows you to determine the MIC (minimum inhibitory concentration) of antibacterial agents. Alamar blue is a redox indicator that changes color from blue to pink in the case of bacterial growth. Resazurin (blue and non-fluorescent) is reduced to resorufin (pink and fluorescent) by living bacteria. Plates are read visually or using fluorescence measurements.

The fluorescence intensity is proportional to the number of live bacteria.

So that a larger MIS fluorimetric value tends to zero, a smaller amount of the product is needed to inhibit the overall growth of bacteria.

The conducted experiments demonstrate that the compounds of this invention are active in inhibiting the growth of M. yibegscio5i5. MIS values are usually between 0.1 and 10 μm, or even between 0.1 and 1 μm. The compounds presented as examples in the patent application under consideration usually have an MIS value of less than 1 μm.

Table C

Table of activities

Activities 12811106 11111111 ba 177711717171717111111110567777117171717111117111111111111111184С1 nynkninnynynyh others: write

Continuation of the table From now on write saw tt saw

MO: not determined

The compounds of the present invention, namely, the compounds corresponding to the formula (I), in addition, have good microbiological characteristics, and are particularly suitable for use in the preparation

B medicines, especially antibiotics with a narrow spectrum of action for the treatment and/or prevention of tuberculosis.

In particular, these antibiotics have an antimicrobial effect against M. (shbegscio5i5 for the treatment and/or prevention of tuberculosis.

Thus, according to other aspects of the invention, the subject of the invention are medicinal products that include a compound of formula (I), or an addition salt of an acid or base of a compound of formula (1).

These drugs are used in therapy, especially in the treatment and/or prevention of tuberculosis.

According to other aspects, the present invention relates to pharmaceutical compositions that include a compound of the present invention as an active ingredient. Said pharmaceutical compositions contain an effective dose of at least one compound of this invention, or a pharmaceutically acceptable salt of said compound and also at least one pharmaceutically acceptable excipient.

These excipients are chosen depending on the pharmaceutical form and the desired method of administration, from the usual excipients known to specialists in this field.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, external, topical, intratracheal, intranasal, transdermal or rectal administration, the active compounds of formula (I) above, or salts thereof, can be administered in a single in a form for administration, in the form of a mixture with standard pharmaceutical excipients, to humans and animals for the prevention or treatment of the above disorders or diseases.

Suitable forms for administration include forms for oral administration such as tablets, soft or hard gelatin capsules, powders, granules and solutions or suspensions for oral administration, forms for sublingual, buccal, intrathecal, intraocular and intranasal administration, forms for administration by inhalation, for

For local, transdermal, subcutaneous, intramuscular or intravenous administration, forms for rectal administration and implants. For local application, the compound according to the present invention can be used in the form of gels, ointments or lotions.

So, for example, a single form for the introduction of a compound according to the present invention in the form of a tablet may contain the following components:

The compound according to the present invention is 50.0 mg

Mannitol 223.15 mg

Croscarmellose sodium 6.0 mg

Corn starch 15.0 mg

Hydroxypropylmethylcellulose 2.25 mg

Magnesium stearate 3.0 mg

There may be specific cases where higher or lower doses are used; such doses do not follow from the context of this invention. According to the usual practice, suitable doses for each patient are determined by the doctor according to the method of administration and the weight and reaction of the particular patient.

According to other aspects, the present invention relates to the use of compounds of formula (I) for the prevention and/or treatment of bacterial infections caused by gram-positive microorganisms and mycobacteria.

In accordance with other aspects, the present invention relates to the use of compounds of formula (1) or their pharmaceutically acceptable salts for the treatment and/or prevention of bacterial infections caused by mycobacteria, such as M. yshbegsiio5i5, M. 5ztedtaiyi5, M. rpPIei, or other microorganisms, such as, for example, Mosagaia Bgaziyepvib5, Mosagaia abze55y5 or

Sogupebasivetit airpiNegia.

Thus, one aspect of the present invention relates to the use of compounds of formula (I) or their pharmaceutically acceptable salts for the treatment and/or prevention of infectious diseases, such as tuberculosis, leprosy, nocardiosis, diphtheria, pulmonary mycobacterial infections, skin mycobacterial infections, atypical mycobacterial infections and mycobacteriosis.

The term "tuberculosis" includes infections caused by bacilli of the tuberculosis complex (M. yibegsshov5iv, M. romiv, and M. aigisapyt), all of which are pathogenic to humans. Pulmonary tuberculosis is undoubtedly the most common and most widespread; this is tuberculosis of the lungs, larynx, trachea and bronchi, tuberculosis of the lymph nodes of the chest, pleural respiratory tuberculosis, primary respiratory tuberculosis and any other respiratory tuberculosis.

Although less common, there are ganglionic tuberculosis and extrapulmonary tuberculosis, tuberculosis of the nervous system, such as tuberculous meningitis, tuberculous leptomeningitis, cerebral tuberculosis and any other tuberculosis of the nervous system, or tuberculosis of the bones or joints, tuberculosis of the urogenital system, lymphadenopathic peripheral tuberculosis, gastrointestinal tuberculosis, peritoneal tuberculosis and/or tuberculosis of the mesenteric lymph nodes, tuberculosis of the skin and subcutaneous tissues, tuberculosis of the eyes or ears or adrenal glands, and disseminated tuberculosis.

The term "leprosy" (Hansen's disease) includes infections caused by Musorasiegisht Iergae: undifferentiated leprosy, tuberculoid leprosy, borderline leprosy, borderline tuberculoid leprosy, lepromatous leprosy, and other forms of leprosy.

The term "diphtheria" includes pharyngeal diphtheria, nasopharyngeal diphtheria, cutaneous diphtheria and also other forms and diphtheria.

The term "nocardiosis" includes pulmonary nocardiosis, cutaneous nocardiosis and other forms

From nocardiosis.

According to other aspects of the invention, the present invention also relates to a method of treating the above-mentioned pathologies, which includes administering to the patient an effective dose of the compound of formula (I).

Claims (17)

FORMULA OF THE INVENTION 1. Compound of formula (1): (c) u and r 1/ no) o, bony that Shche nya enenannnta . Rasch / Tl (c) "o o no" ped y - ;-- o z (o vIoM on ka ; (I) where: MU is a hydrogen atom, the group -(C-0)-MA2Az or the group -(" C0-O)-O-Biv; 7 represents: a hydrogen atom, a -C:-C-alkyl group, which is unsubstituted or substituted by one or more of the Ba groups, a -C37-cycloalkyl group, which is an unsubstituted or substituted group - МН-(С-ОО)-Б:» or the group -МН-5О2-Ноо, the group -C3-ε-heterocycloalkyl, group -МН-(С-О)-Вб5; B: represents a hydrogen atom, a -Cg2-e-alkenyl group, a -Cg-e-alkynyl group or a -Cg-6-alkyl group that is unsubstituted or substituted by a -Ci-4-fluoroalkyl group or a heteroaryl group that is unsubstituted or substituted by a 3-(3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-ylmethyl group; B: represents a hydrogen atom or a -C:-C-alkyl group; Az represents: a -C3-;-cycloalkyl group, which is unsubstituted or substituted by a -C.:-C-alkyl group, a substituted -MH-5O2-B2h group, a heteroaryl group, an unbranched or branched group -C:i-e- -alkyl, which is an unsubstituted or substituted group selected from: the group -MH-Bb, the group -MH-50»2-B»?, the group -MH-(C-O)-Bb, the group -C3-;-cycloalkyl , which is an unsubstituted or substituted -C3-e-heterocycloalkyl group, a -C3-e--heterocycloalkyl group, an aryl group, which is unsubstituted or substituted by one or more of the groups independently selected from the halogen atom and the -C:-4- group fluoroalkyl, a heteroaryl group which is unsubstituted or substituted by a -Ci-3-alkyl group, a -Ci-4- alkoxy group, a -C:1-4-fluoroalkyl group or a -C3-6-heterocycloalkyl group, or, alternatively, one or more of the -C:1-4-alkoxy groups; or, alternatively, 5 and Bz, together with the nitrogen atom to which they are attached, form a C3-6-heterocycloalkyl group selected from: aziridine, azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine; and the specified heterocycloalkyl group is an unsubstituted or substituted heteroaryl group, and the specified heteroaryl group is an unsubstituted or substituted -C1-4-fluoroalkyl group; Va independently represents a group selected from: a hydroxyl group, deuterium, a halogen atom, a -C3--cycloalkyl group, an aryl group that is unsubstituted or substituted by one or more of the -No groups, a heteroaryl group, a -C3-e- group -heterocycloalkyl, -C:i-4-alkyl groups, -(C-0)-MH-B'o groups, -MH-Bich groups, -MH-(C-OO0)-Bch2 groups or -MH(5O13 )-Cart; B5 is a heteroaryl group; Ve is a heteroaryl group that is unsubstituted or substituted by one or more halogen atoms; AV; represents a -C1-4-fluoroalkyl group, an aryl group or a heteroaryl group, and the specified aryl and heteroaryl groups are unsubstituted or substituted by one or more of the Ag groups; Bv represents a heteroaryl group that is unsubstituted or substituted by one or more of the groups B"; Bo represents a halogen atom, a -Ci-- alkoxy group, a formyl group (CHO) or a -C1-4- alkyl group, which is unsubstituted or substituted by a hydroxyl group; Vio represents a heteroaryl group that is unsubstituted or substituted by a -Ci-C-alkyl group; Vii represents: a -C3-o-heterocycloalkyl group, which is unsubstituted or substituted by one or more oxide groups, a heteroaryl group or an aryl-C:i--alkyl group, and the specified heteroaryl or aryl group is unsubstituted or substituted by one or more from groups independently selected from a halogen atom, a hydroxyl group, a nitro group and a -C.-3-alkyl group; Vig is: a -Ci---------------------Alkoxy group, a -Ci-4---alkyl group, which is unsubstituted or substituted by a group -MA:1«H:5 or a heteroaryl group, and the specified heteroaryl group is an unsubstituted or substituted group - C-C-alkyl, a heteroaryl group, which is unsubstituted or substituted by one or more of the groups selected from the hydroxyl group and the -C-C-alkyl group; Wiz represents: a -C:---alkyl group, a -C1-4-fluoroalkyl group, an aryl group that is unsubstituted or substituted by a nitro group, or a heteroaryl group that is unsubstituted or substituted by a group -MAch6Bi17; Ba, Viv, Viv and Vi7 each independently represents: a hydrogen atom or a -Ci-4-alkyl group; Viv is a -Ci-4-alkyl group or a benzyl group; B" represents an aryl group or a heteroaryl group; Hg is a -Ci-4-alkyl group or an aryl group; Hg represents an aryl group; B: represents: a halogen atom, a -Ci---Alkoxy group, a -C1-4-fluoroalkyl group, a -OCE group, a nitro group, a -MH group, a -MNON»C3 group; Ag represents: a hydroxyl group, a -C:-C-alkyl group. 2. Compound according to claim 1 of the formula (IA): о (о) in. For HU had, vni b) o, On, a" i i, eq vvi i SU o U o NO t, h o gi in t8-- y t o - ( vioM on M y y (IA) where: Vi, B", Bz and 7 have the values indicated in claim 1. Зо 3. The compound according to claim 1 of the formula (IV): (6) o, OO, My a p, channel and (U o is (c) and U / (c) (c) o -vo-- 5 t Ge) - (v.oM on M Kk and (V) where: B: 7 have the values specified in claim 1. 4. Compound according to claim 1 of formula (I): о (9) Й У св, У uke о, about in p; shchi ce ", pnnnnnannit o o er o i that ) te, , / (c) (9) o v 7v-- - o s o vIoM on ra y (i) where: Vi, Viv and 7 have the values specified in claim 1. 5. The compound of formula (I) according to claim 1, which differs in that: U represents a hydrogen atom, a -(C-0)-MA2Az group or a -"C-0)-OMe group; 7 represents: a hydrogen atom, a -C:-C-alkyl group, which is unsubstituted or substituted by one or more of the Ba groups, a cyclopropyl group, a cyclobutyl group, a 3-(benzoylamino)cyclobutyl group, a 3-(pyrazin-2-ylcarbonyl)amino|Ycyclobutyl group, 3 -Kmethylsulfonyl)amino-cyclobutyl group, 3-N-phenylsulfonyl)amino-cyclobutyl group, cyclopentyl group, cyclohexyl group, tetrahydro-2H-pyranyl group, -MH-(C-O)-B5 group; B: represents a hydrogen atom, an ethyl group, 2,2,2-trifluoroethyl group or methyl group, which is unsubstituted or substituted by 1,2,3-triazole group, substituted by 3-(3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-ylmethyl group; Bg represents a hydrogen atom or a methyl group, Az represents: cyclohexyl group, 1-"(phenylsulfonyl)amino|methylcyclohexyl group or 1-"Cphenylsulfonyl)amino|methyl)cyclopentyl group, 5,6,7,8-tetrahydroquinoline-5 - fig a group or an unbranched or branched C-4-alkyl group, which is an unsubstituted or substituted group selected from: -MH-Hv, -MH-50»2-B?7, -MH-(C-O)-Bv, 1-morpholin-4-ylcyclopentyl group, Zo tetrahydro-2H-pyranyl group, tetrahydrofuranyl group or morpholin-4-yl group, phenyl group, which is unsubstituted or substituted by one or more of the groups independently selected from the chlorine atom and the -CEz group , 1H-pyrrolo|(2,3-b|Ipyridinyl group, 4-methyl-5,6,7,8-tetrahydroquinazolin-2-yl group, 6-methoxy-1H-benzimidazol-2-yl group, pyridinyl group, which is unsubstituted or substituted by a -CE3 group or a morpholin-4-yl group, or, alternatively, one or more of the methoxy groups; or, alternatively, P" and Bz, together with the nitrogen atom to which they are attached, form a -C3-6- heterocycloalkyl group selected from: azetidine, morpholine, 4-(5-"(trifluoromethyl)pyridin-2-yl| Ba is independently a group selected from: a hydroxyl group, deuterium, a fluorine atom, a cyclopropyl group, a phenyl group, which is unsubstituted or substituted by one or more of the groups independently selected from a fluorine atom, a methoxy group, a -CH2HOH group and -CHO group, pyridyl group, a morpholinyl group, a tetrahydro-2H-pyranyl group, a methoxy group, a -(C-0)-MH-A:o group, a -MH-Vich group, a -MH-(C-0)-Bi12 group or a -MH(ZO» group 2)-Visa; B5 is a pyridyl group; Bb is a quinolyl group, and the specified quinolyl group is unsubstituted or substituted by a chlorine atom; IN; represents a -SEz group, phenyl, pyridyl, pyrazolyl, 1H-pyrrolo|2,3-b|Ipyridyl or indolyl group, and the specified phenyl, pyridyl, pyrazolyl, 1H-pyrrolo|2,3-B|Ipyridyl or indolyl groups are unsubstituted or substituted by one or more of groups B; Bv represents a pyrazinyl group, and the specified pyrazinyl group is unsubstituted or substituted by one or more of the groups B"; Vio is a 1,8-naphthyridinyl group substituted with a methyl group; Vii represents a tetrahydrothiophene-1,1-dioxide, quinolyl, pyridyl or benzyl group, and said quinolyl, pyridyl or benzyl groups are unsubstituted or substituted by a chlorine atom, a hydroxyl group, a nitro group or a methyl group; Vig represents: a tert-butoxy group, a C 1 -alkyl group, which is an unsubstituted or substituted group selected from: a group -MA:4B'z, a pyridyl or pyrazolyl group, and the indicated pyridyl or pyrazolyl group is an unsubstituted or substituted methyl group, pyrazinyl or pyridyl, which are unsubstituted or substituted by one or more of the groups selected from the hydroxyl group and the metal group; Wiz represents: a group -SEz, a phenyl group, which is unsubstituted or substituted by a nitro group, or a pyridyl group, which is unsubstituted or substituted by a group -Мах6В'?7; Koo) Ba, Viv, Viv and Vi7 each independently represents: a hydrogen atom, a methyl group or an isopropyl group; AB represents: a fluorine atom, a chlorine atom, a methoxy group, a -CEz group, a -OSE group, a nitro group, a -MH group, a -MNON»Zz group; Ag represents: a hydroxyl group, a methyl group. 6. The compound of formula (I) according to claim 1, which differs in that: U represents a hydrogen atom or the group -(C-0)-MA2Bz; 7 represents: hydrogen atom, methyl group, isopropyl group, 2,2-dimethylpropyl group, COz group, 2-fluoroethyl group, cyclopropylmethyl group, 2-phenylethyl group, (7-methyl-1,8-naphthyridin-2-yl )amino|-4-oxobutyl group, 2-ISHK2-nitrophenyl)sulfonyl|amino)ethyl group, cyclopropyl group, tetrahydro-2H-pyranyl group; B: represents a hydrogen atom, an ethyl group, a 2,2,2-trifluoroethyl group or a methyl group; Bg is a hydrogen atom or a methyl group; Az represents: (516) a methyl group, 2-S(2,6-difluorophenyl)sulfonyl|amino)-1,1-dimethylethyl group, 1,1-dimethyl-2-(C4-trifluoromethyl)phenyl|sulfonyl)amino)ethyl group, 2-S2-fluorophenyl )sulfonyl|amino)-1,1-dimethylethyl group, 1,1-dimethyl-2-(C2-(trifluoromethoxy)phenyl|sulfonyl)amino)ethyl group, 1,1-dimethyl-2-(C4-(trifluoromethoxy) )phenyl|sulfonyl)amino)ethyl group, 2-methyl-1-Kphenylsulfonyl)amino|propan-2-yl group, 2-methyl-1-(5-nitro-1H-pyrazol-4-yl)usulfonyl|amino )propan-2-yl group, 2-methyl-1-(trifluoromethyl)sulfonyl|Iamino)zpropan-2-yl group, 2-methyl-1-(2-nitrophenyl)sulfonyl|amino)propan-2-yl group , 1--K5-hydroxypyrazin-2-yl)/ucarbonyl|amino)-2-methylpropan-2-yl group, 1,1-dimethyl-2-morpholin-4-ylethyl group, benzyl group, 2-(4- pyridyl)ethyl group. 7. The compound of formula (I) according to any one of claims 1-6, which differs in that it corresponds to any one of the following compounds: (28,35,48,58,75,95,105,118,125,138)-7-(benzylcarbamoyl )oxy|-2-(1-(28,38,48,5H8,68)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl|oxy)propan-2-yl )-10-1(25,38,6НА)-3-hydroxy-4-(methoxyimino)-b-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13- hexamethyl-6,14-dioxo-12-(25,55,7H)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxy)oxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7-(benzylcarbamoyl)oxy)|-2-(1-(28,38,48,5H8,68)-5-hydroxy-3,4-dimethoxy- b-methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-((25,38,6H8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2- yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14-dioxo-12-(25,58,78)-2,4,5-trimethyl-1,4-oxazepan-7 -yl|oxydoxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-12-(25,78)-4-cyclopropyl-2,5-dimethyl-1,4-oxazepan-7-yl|oxy)-2-(1- -(28,38,4Н,5Н,6НА)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2Н-pyran-2-yl|Ioxy)upropan-2-yl)-10-((25, 38,6НА)-3-hydroxy-4-(methoxyimino)-b-methyltetrahydro-2H-pyran-2-yl|oxy)-7-4(1-((5-hydroxypyrazin-2-yl)ucarbonyl|amino) -2-methylpropan-2-ylcarbomoyl|oxy)-3,5,7,9,11,13-hexamethyl-6b,4-dioxooxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7-(benzylcarbamoyl)oxy|-12-1(25,58,78)-2,5-dimethyl-1,4-oxazepan-7-yl|oxy )-2-(1-((2НА,3А4Н,5Н,6А)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2Н-pyran-2-yl|oxy)propan-2-yl)- 10-(25,38,6H8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b ,14-dioxooxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-2-(1-((28,38,48,58,6НА)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran- 2-yl|oxypropan-2-yl)-10-((25,38,6H8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5 . ,5-trimethyl-1,4-oxazepan-7-yl|oxidoxacyclotetradecan-4-yl-3-methylbutonate; (28,35,48,58,75,95,105,118,125,138)-7-(benzylcarbamoyl)oxy|-12-( 25,78)-4-cyclopropyl-2,5-dimethyl-1,4-oxazepan-7-yl|Ioxy)-2-(1-(28,38,4Н,5Н,6НА)-5-hydroxy-3 ,4-dimethoxy-6- methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-((25,38,6H8)-3-hydroxy-4-(methoxyimino)-6- methyltetrahydro-2H -pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14-dioxooxacyclotetradecane-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138 )-7-(benzylcarbamoyl)oxy|-12-(25,78)-2,5-dimethyl-4-((Hz)methyl-1,4-2-(1-oxazepan-7-yl|oxy)- 2-(1-((28,38,48,58,6НА)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl|oxyupro pan-2-yl)-10-((25,38,6H8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9 ,11,13-hexamethyl-b,14-dioxooxacyclotetradecane-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7-(dimethylcarbamoyl)oxy|-2-(1--(28,38,48,5Н,68)-5-hydroxy-3,4-dimethoxy- b-methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-((25,38,6H8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2- yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14-dioxo-12-(25,58,78)-2,4,5-trimethyl-1,4-oxazepan-7 -yl|oxydoxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7-(benzylcarbamoyl)oxy|-12-(25,78)-2,5-dimethyl-4-(2- ((2-nitrophenyl)sulfonyl)amino )ethyl)-1,4-oxazepan-7-yl|oxy)-2-(1-((28,38,48,5Н8,6НА)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2Н -pyran-2-yl|oxypropan-2-yl)-10-((25,38,6H8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)- 3,5,7,9,11,13-hexamethyl-b,14-dioxooxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7-(benzylcarbamoyl)oxy|-12-(25,78)-4-(2-fluoroethyl)-2,5-dimethyl-1,4-oxazepan- 7-yl|Ioxy)-2-(1-(28,38,4Н,5Н,6НА)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl|oxypropane-2- yl)-10-((25,38,6H8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13 -hexamethyl-b,14-dioxooxacyclotetradecane- 4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7-(benzylcarbamoyl)oxy|-12-(25,78)-2,5-dimethyl-4-(4-(7-methyl-1,8- naphthyridin-2-yl)amino|-4-oxobutyl)-1,4-oxazepan-7-yl|oxy)-2-(1- (en, H, bA)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy)upropan-2-yl)-10-(25,38,68)Z -hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13- hexamethyl-6b,14-dioxooxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7-((benzylcarbamoyl)oxy|-12-(25,78)-(2,2-dimethylpropyl)-2,5-dimethyl-1,4-oxazepane -7-yl|oxy)-2-(1--(28,3H8,4H8,5H,6H)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxyupropane- 2-yl)-10-S(25,38,6H8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11 ,13-hexamethyl-6,14- dioxooxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,5H8,75,95,105,118,125,138)-12-((25,78)-2,5-dimethyl-4-(2-phenylethyl)-1,4-oxazepan-7-yl|oxy)- 2-(1--(28,3H8,48,5НА,6НА)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl|Ioxy)upropan-2-yl)-10 -((25,38,6НА)-3-hydroxy-4-(methoxyimino)-b-methyltetrahydro-2H-pyran-2-yl|oxy)-7-4(1-((5-hydroxypyrazin-2-yl )ucarbonyl|amino)-2-methylpropan-2-ylcarbamoyl|oxy)- 3,5,7,9,11,13-hexamethyl-b,14-dioxooxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-2-(1-((28,38,48,58,6НА)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran- 2-yl|oxypropan-2-yl)-10-((25,38,6H8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5 ,7,9,11,13-hexamethyl-7-4 (2-methyl-1-((5-nitro-1H-pyrazol-4-yl)usulfonyl|amino)propan-2-yl)ucarbamoyl|oxy) -6,14-dioxo-12-1(25,78)-2,4,5- trimethyl-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7-hydroxy-2-(1--(28,38,48,5Н,6Н8)-5-hydroxy-3,4-demethoxy-b-methyltetrahydro- 2H-pyran-2-yl|oxy)upropan-2-yl)-10-S(25,38,6H8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl| oxy)-3,5,7,9,11,13-hexamethyl-b,14-dioxo-12- ((25,58,78)-2,4,5-trimethyl-1,4-oxazepan-7- ilioxyioxacyclotetradecane-4-yl-3-methylbutanoate; Zo (28,35,48,58,75,95,105,118,125,138)-2-(1-((28,38,48,58,6НА)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran -2-yl|oxypropan-2-yl)-10-((25,38,6H8)-3-hydroxy-4-(methoxyimino)-6- methyltetrahydro-2H-pyran-2-yl|oxy)-3, 5,7,9,11,13-hexamethyl-7-((2-methyl-1-(Ctrifluoromethyl)sulfonyl|amino)propan-2-yl/ucarbamoyl|oxy)-6,14-dioxo-12-(( 25,78)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-12-(25,78)-2,5-dimethyl-4-(2-phenylethyl)-1,4-oxazepan-7-yl|oxy)-7 -hydroxy-2-(1--(28,38,4Н,5Н,6НА)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2Н-pyran-2-yl|oxy)propan-2-yl )-10-(25,38,6H8)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl -b,14-dioxooxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-2-(1-((28,38,48,58,6НА)-5-hydroxy-3,4-dimethoxy-6- methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-((25,38,6H8)-3-hydroxy-4-(methoxyimino)-6- methyltetrahydro-2H-pyran-2-yl| oxy)-3,5,7,9,11,13-hexamethyl-7--(2-methyl-1-(((2-nitrophenyl)sulfonyl|amino)propan-2-yl)ucarbamoyl|oxy)-6 ,14-dioxo-12-((25,58,78)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48 ,58,75,95,105,118,125,138)-2-(1-((28,38,48,58,6НА)-5-hydroxy-3,4-dimethoxy-6- methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-((25,38,6H8)-3-hydroxy-4-(methoxyimino)-6- methyltetrahydro-2H-pyran-2-yl| oxy)-3,5,7,9,11,13-hexamethyl-7--(2-methyl-1-(((2-nitrophenyl)sulfonyl|amino)propan-2-yl)ucarbamoyl|oxy)-6 ,14-dioxo-12-((25,55,7 8)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl-3-methylbutanoate; (28,35, 48,58,75,95,105,118,125,138)-2-(1-((28,38,48,58,6НА)-5-hydroxy-3,4-dimethoxy-6- methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-((25,38,6H8)-3-hydroxy-4-(methoxyimino)-6- methyltetrahydro-2H-pyran-2-yl| oxy)-3,5,7,9,11,13-hexamethyl-7-(((2-methyl-1- Cphenylsulfonyl)amino|propan-2-ylcarbamoyl)oxy|-6,14-dioxo-12-( 25,55,78)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-2 -(1-((28,38,48,58,6НА)-5-hydroxy-3,4-dimethoxy-6- methyltetrahydro-2H-pyran-2-yl|oxypropan-2-yl)-10-((25,38,6H8)-3-hydroxy-4-(methoxyimino)-6- methyltetrahydro-2H-pyran-2-yl| oxy)-3,5,7,9,11,13-hexamethyl-7-(((2-methyl-1- Cphenylsulfonyl)amino|propan-2-ylcarbamoyl)oxy|-6,14-dioxo-12-( 25,58,78)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7 -(31,1-dimethyl-2- bo Cphenylsulfonyl)amino|ethylcarbamoyl)oxy|-2-(2-(28,38,48,5H8,68)-5-hydroxy-3,4-dimethoxy- b-methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10-(25,38,6НА)-3-hydroxy-4-(methoxyimino)- b-methyltetrahydro-2H-pyran-2- yl|oxy)-12-((25,78)-4-isopropyl-2,5-dimethyl-1,4-oxazepan-7-yl|oxy)-3,5,7,9,11,13-hexamethyl -b,14-dioxooxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,1055118,125,138)-12-((25,58,7 H)-4-(cyclopropylmethyl)-2,5-dimethyl-1,4- oxazepan-7-yl|oxy)-7-((1,1-dimethyl-2-(phenylsulfonyl)amino|ethylcarbamoyl)oxy|-2-(2- (en, H,5H,6A)-5-hydroxy- 3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10-(25,38,68)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro- 2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14-dioxooxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-12-((25,78)-4-(cyclopropylmethyl)-2,5-dimethyl-1,4- oxazepan-7-yl|oxy)-7-((1,1-dimethyl-2-(phenylsulfonyl)amino|ethylcarbamoyl)oxy|-2-(2- (en, H,5H,6A)-5-hydroxy- 3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10-(25,38,68)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro- 2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14-dioxooxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7-(31,1-dimethyl-2- Cphenylsulfonyl)amino|ethylcarbamoyl)oxy|-12-((25,7 8)-2,5-dimethyl-4-(tetrahydro-2H-pyran-4-yl)-1,4-oxazepan-7-yl|oxy )-2-(2-((2А8,3А,4Н,5Н,6А)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2Н-pyran-2-yl|oxy)-1-methylethyl)- 10-(25,38,6НА)-3-hydroxy-4-(methoxyimino)-b-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b ,14-dioxooxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-12-(25,55,7H8)-4-(cyclopropylmethyl)-2,5-dimethyl-1,4-oxazepan-7-yl|oxy)-7 -((1,1-dimethyl-2-(phenylsulfonyl)amino|ethylcarbamoyl)oxy|-2-(2- (en, H,5H,6A)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro- 2H-pyran-2-yl|oxy)-1-methylethyl)-10-(25,38,68)-3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy) - 3,5,7,9,11,13-hexamethyl-b,14-dioxooxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7-(31,1-dimethyl-2-Cphenylsulfonyl)amino|ethylcarbamoyl)oxy|-12-((25,58,78)-4-(2, 2-dimethylpropyl)-2,5-dimethyl-1,4-oxazepan-7-yl|oxy)-2-(2-(28,3Н8,4Н8,5НА,6А)-5-hydroxy-3,4-dimethoxy -6- methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10-(25,38,6НА)-3-hydroxy-4-(methoxyimino)-6- methyltetrahydro-2H-pyran-2 -yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14-dioxooxacyclotetradecane- Ko) 4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7-(31,1-dimethyl-2-Cphenylsulfonyl)amino|ethylcarbamoyl)oxy|-12-((25,7 8)-4-(2,2 -dimethylpropyl)-2,5-dimethyl-1,4-oxazepan-7-yl|oxy)-2-(2-((2НА,3А4Н,5Н,6А)-5-hydroxy-3,4-dimethoxy-6 -methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10-((25,38,6НА)-3-hydroxy-4-(methoxyimino)-b-methyltetrahydro-2H- pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14-dioxooxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7-((1,1-dimethyl-2-morpholin-4-ylethylcarbamoyl|oxy)-2- (2-2, 4Н,5Н,6А)-5 -hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10-(25,38,68)-3-hydroxy-4-(methoxyimino)-6 -methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-6b,14-dioxo-12-(25,7 8)-2,4,5-trimethyl -1,4-oxazepan-7- yl|oxydoxacyclotetradecane-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7-((2-(2,6-difluorophenyl)sulfonyl|amino)-1,1- dimethylethyl)carbamoyl|oxy)-2-(2-( 28,38,48,58,6НА)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10-(25,38,6НА) -3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14-dioxo-12-S( 25,78)-2,4,5- trimethyl-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7-(11,1-dimethyl-2-(C4-(trifluoromethyl)phenyl|sulfonyl)amino)ethylcarbamoyl)ioxy)-2-(2-(28, 38,48,5H8,68)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10-((25,38,6НА)- 3-hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14-dioxo-12- ((25,78)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7 -((2-(2-fluorophenyl)sulfonyl|amino)-1,1-dimethylethyl)carbamoyl|oxy)-2-(2-((28,38,48,58,6НА)-5-hydroxy-3, 4-dimethoxy-6- methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10-(25,38,6НА)-3-hydroxy-4-(methoxyimino)-6- methyltetrahydro-2H- pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14-dioxo-12-S(25,78)-2,4,5- trimethyl-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7-(11,1-dimethyl-2-(CC2-(trifluoromethoxy)phenyl|sulfonyl)amino)ethylcarbamoyloxy)-2-(2-(28,38, 48,58,6НА)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10-((25,38,6НА)-3- hydroxy-4-(methoxyimino)-6-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-b,14- dioxo-12-(25,78)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7-(11,1-dimethyl-2-(C4-(trifluoromethoxy)phenyl|sulfonyl)amino)ethylcarbamoyl)oxy)-2-(2-(28, 38,48,58,6НА)-5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10-((25,38,6НА)- 3- hydroxy-4-(methoxyimino)-b-methyltetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-6,14-dioxo-12-(25, 78)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7-(31,1-dimethyl-2-Cphenylsulfonyl)amino|ethylcarbamoyl)oxy|-2-(2-(28,38,48,5H8,68) -5-hydroxy-3,4-dimethoxy-b-methyltetrahydro-2H-pyran-2-yl|oxy)-1-methylethyl)-10-((25,38,6H8)-3-hydroxy-b-methyl- 4-((2,2,2-trifluoroethoxy)imino|tetrahydro-2H-pyran-2-yl|oxy)-3,5,7,9,11,13-hexamethyl-6b,14-dioxo-12- ( (25,78)-2,4,5-trimethyl-1,4-oxazepan-7-yl|oxyyoxacyclotetradecan-4-yl-3-methylbutanoate; (28,35,48,58,75,95,105,118,125,138)-7 -(31,1-dimethyl-2-Cphenylsulfonyl)amino|ethylcarbamoyl)oxy|-10-1(25,38,68)-4-(ethoxyimino)-3-hydroxy-6- methyltetrahydro-2H-pyran-2- yl|oxy)-2-(2-((28,38,48,5H,6A)-5-hydroxy-3,4-dimethoxy-6-methyltetrahydro-2H-pyran-2-yl|oxy)-1- methylethyl)-3,5,7,9,11,13-hexamethyl-b,14-dioxo-12- ((25,58,78)-2,4,5-trimethyl-1,4-oxazepan-7- ilyoxyioxacyclotetradecane-4-yl-3-methylbutanoate. 8. The method of obtaining the compound of formula (I) according to claim 1, where M represents the group -(С-О)-MA2Az, which differs in that: the compound of formula (IV): (c) in с -он о, Он, no i p, etan vann vvi (U o U she BUT. t, h o o b or y x Ge) r. ( vom Ge M Z y , (c) where Ni and 7 have the values indicated in claim 1 for compounds of formula (I), subject to interaction with the compound of formula (II) NMR" , where P» and Az have the values specified in claim 1 for compounds of formula (I), in the presence of a carbonyl derivative and a base. 9. The method of obtaining the compound of formula (I) according to claim 1, where M represents the group -(С-О)-МА2Аз, which differs in that: p-1) the compound of formula (М): o (c) and U mal , Ku Te) o, Ok, that To p, senati (U o is o . NOpe- M. u / (c) (c) o -oo-- - Kya o s. no vIoM on no y shcha de Vi, B» and Az have the values specified in claim 1 for compounds of formula (I), are subjected to interaction with an oxidizing agent, to obtain a compound of formula (MI): o c) y U ml, Ku o o, o, it -e t, senate (U o u o a. NOpe- a, u / c) c) o -- o o-- 2 o- vIOM ON o ; (MI) p-d) the compound of the formula (MI) obtained in this way is subjected to interaction with the compound of the formula (MI): ach; (mi) where 7 has the values specified in claim 1 for the compound of formula (I), in the presence of a reducing agent. 10. The method of obtaining the compound of the formula (I) according to claim 17, where M is a hydrogen atom, which differs in that: c-1) the compound of the formula (MIP): (6) it is in Oz, shcha i "i, senat vvi (U z (o) and NOne- o, u / (c) (c) o -o o-- , o I no vIoM Gen! also (M) where B: has the values indicated in claim 1 for the compound of the formula ( I), are subjected to interaction with an oxidizing agent, to obtain a compound of the formula (IX): (c) sleep in On, 7 Also "i, penal (3 о у о . НОне- о, У / (c) (c) о - o-- y t o - ud vIoM on o ; (Ih) c-2) the compound of formula (IX) obtained in this way is subjected to interaction with the compound of formula (MI): 2МН, (Ми) where 7 has the values specified in claim 1 for the compound of formula (I), in the presence of a reducing agent. 11. The method of obtaining the compound of formula (I) according to claim 1, where U represents the group -(С-0)-О-В!iv, which differs in that: the compound of formula (XXI) (c) g M m i- оо х- о, Ок, и" ne "и, sect in (U o E (in) "Z non. o, s in (in) (in) o b 78-- I Ka o - ( vom on M 27 ; (XXI) where 7 and B have the values specified in claim 1 for the compound of formula (I), are subjected to interaction with the alcohol of the formula HO-Biv (XXIII), where Biv has the values specified in claim 1 for the compound of formula (I), in the presence foundations. 12. Compound of formula (M): o (c) y U mal, KU Te) o, o i" Still "i, sela nt vi (U o E (c) "Z NO"che- o, s u (c ) (c) o -o to-- , o Y no PTO on no what where: Vy, B" and Az have the values specified in claim 1 for the compounds of formula (1). 13. Compound of the formula (MI): (c) s-oN o,, On, NE" This is 1, MI c) Ge) u o) and NOpe-,, cho (c) (c) o -9 o-- ; --o - no kom on No; (We) where: A: have the values specified in claim 1 for the compounds of formula (1). 14. Medicinal product, which is characterized in that it includes a compound of formula (I) according to any one of claims 1-7 in the form of a base or in the form of an acid addition salt. 15. A pharmaceutical composition, which is characterized in that it includes a compound of formula (1) according to any one of claims 1-7 in the form of a base or an acid addition salt and also at least one pharmaceutically acceptable excipient. 16. Use of the compound according to any one of claims 1-7 for the prevention and/or treatment of bacterial infections caused by gram-positive microorganisms and mycobacteria. 17. Use of a compound according to any one of claims 1-7 for the prevention and/or treatment of infectious diseases selected from tuberculosis, leprosy, nocardiosis, diphtheria, pulmonary mycobacterial infections, skin mycobacterial infections, atypical mycobacterial infections and mycobacteriosis.